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{\*\bkmkstart filing_1}{\*\bkmkend filing_1}{\*\bkmkstart doc_1_1}{\*\bkmkend doc_1_1}\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\brdrb\brdrs\sa22\cf1\f51\fs2\b\ql \~\par\pard\plain\sb66\cf1\f51\fs34\b\qc UNITED STATES\par\pard\plain\cf1\f51\fs34\b\qc SECURITIES AND EXCHANGE COMMISSION\par\pard\plain\cf1\f51\fs20\b\qc Washington, D.C. 20549\par\pard\plain\brdrb\brdrs\li924\ri924\cf1\f51\fs6\qc \~\par\pard\plain\sb132\cf1\f51\fs34\b\qc FORM 10-K\par\pard\plain\brdrb\brdrs\li924\ri924\cf1\f51\fs6\qc \~\par\pard\plain\sb66\cf1\f51\fs18\b\ql (Mark One)\par\pard\plain\cf1\f51\fs6\ql \~
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\pard\plain\intbl\cf1\f53\fs20\ql \cell\pard\plain\intbl\cf1\f51\fs20\b\ql ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934\cell{
{\trowd\cellx432\cellx10800\trrh248\row}}}\pard\plain\sb132\cf1\f51\fs18\b\qc For the Fiscal Year Ended December\~31, 2018\par\pard\plain\sb132\cf1\f51\fs18\b\qc OR\par\pard\plain\cf1\f51\fs4\ql \~
\par\pard\plain
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\pard\plain\intbl\cf1\f53\fs20\ql \cell\pard\plain\intbl\cf1\f51\fs20\b\ql TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF\plain\intbl\cf1\f51\fs20\b\ql 1934\cell{
{\trowd\cellx432\cellx10800\trrh495\row}}}\pard\plain\sb66\cf1\f51\fs18\b\qc For the Transition Period from\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~ to\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\~\par\pard\plain\sb66\cf1\f51\fs18\b\qc Commission File Number: 001-38085\par\pard\plain\brdrb\brdrs\li924\ri924\cf1\f51\fs6\qc \~\par\pard\plain\sb66\cf1\f51\fs44\b\qc Ovid Therapeutics Inc.\par\pard\plain\cf1\f51\fs18\b\qc (Exact name of Registrant as specified in its charter)\par\pard\plain\brdrb\brdrs\li924\ri924\cf1\f51\fs6\qc \~\par\pard\plain\cf1\f51\fs6\ql \~
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\pard\plain\intbl\cf1\f51\fs18\b\qc Delaware\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 2834\cell\pard\plain\intbl\cf1\f51\fs18\ql \~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc 46-5270895\cell{
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\pard\plain\intbl\cf1\f51\fs16\b\qc (State or Other Jurisdiction of\par\pard\plain\intbl\cf1\f51\fs16\b\qc Incorporation or Organization)\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc (Primary Standard Industrial\par\pard\plain\intbl\cf1\f51\fs16\b\qc Classification Code Number)\cell\pard\plain\intbl\cf1\f51\fs16\ql \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc (I.R.S. Employer\par\pard\plain\intbl\cf1\f51\fs16\b\qc Identification Number)\cell{
{\trowd\cellx3456\clvertalb\cellx3563\cellx7127\clvertalb\cellx7234\cellx10800\trrh396\row}}}\pard\plain\cf1\f51\fs6\b\qc \~\par\pard\plain\cf1\f51\fs18\b\qc 1460 Broadway, Suite 15044\par\pard\plain\cf1\f51\fs18\b\qc New York, New York 10036\par\pard\plain\cf1\f51\fs18\b\qc (646) 661-7661\par\pard\plain\cf1\f51\fs16\b\qc (Address, Including Zip Code, and Telephone Number, Including Area Code, of Registrant\u8217?s Principal Executive Offices)\par\pard\plain\sb66\cf1\f51\fs18\b\qc Securities registered pursuant to Section\~12(b) of the Act:\par\pard\plain\cf1\f51\fs6\ql \~
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs16\b\qc Title\~of\~Each\~Class\cell\pard\plain\intbl\cf1\f51\fs16\qc \~\cell\pard\plain\intbl\cf1\f51\fs16\b\qc Name of Each Exchange on Which Registered\cell{
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\pard\plain\intbl\cf1\f51\fs18\b\qc Common\~Stock,\~par\~value\~$0.001\~per\~share\cell\pard\plain\intbl\cf1\f51\fs18\qc \~\cell\pard\plain\intbl\cf1\f51\fs18\b\qc Nasdaq Global Select Market\cell{
{\trowd\clbrdrt\brdrs\brdrcf1\cellx5292\clvertalb\cellx5507\clbrdrt\brdrs\brdrcf1\cellx10800\trrh240\row}}}\pard\plain\sb66\cf1\f51\fs18\b\qc Securities registered pursuant to Section\~12(g) of the Act: None\par\pard\plain\brdrb\brdrs\li924\ri924\cf1\f51\fs6\qc \~\par\pard\plain\sb66\fi528\cf1\f51\fs17\ql Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.\~\~\~\~Yes\~\plain\cf1\f53\fs17\ql \plain\cf1\f51\fs17\ql \~\~\~\~No\~\plain\cf1\f53\fs17\ql \par\pard\plain\sb66\fi528\cf1\f51\fs17\ql Indicate by check mark if the registrant is not required to file reports pursuant to Section\~13 or 15(d) of the Securities Act.\~\~\~\~Yes\~\plain\cf1\f53\fs17\ql \plain\cf1\f51\fs17\ql \~\~\~\~No\~\plain\cf1\f53\fs17\ql \par\pard\plain\sb66\fi528\cf1\f51\fs17\ql Indicate by check mark whether the registrant (1)\~has filed all reports required to be filed by Section\~13 or 15(d) of the Securities Exchange Act\plain\cf1\f51\fs17\ql of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2)\~has been subject to the\plain\cf1\f51\fs17\ql filing requirements for the past 90 days.\~\~\~\~Yes\~\plain\cf1\f53\fs17\ql \plain\cf1\f51\fs17\ql \~\~\~\~No\~\plain\cf1\f53\fs17\ql \par\pard\plain\sb66\fi528\cf1\f51\fs17\ql Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule\plain\cf1\f51\fs17\ql 405 of Regulation S-T (\u167? 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to\plain\cf1\f51\fs17\ql submit such files).\~\~\~\~Yes\~\plain\cf1\f53\fs17\ql \plain\cf1\f51\fs17\ql \~\~\~\~No\~\plain\cf1\f53\fs17\ql \par\pard\plain\sb66\fi528\cf1\f51\fs17\ql Indicate by check mark if disclosure of delinquent filers pursuant to Item\~405 of Regulation S-K (\u167? 229.405) is not contained herein, and\plain\cf1\f51\fs17\ql will not be contained, to the best of the registrant\u8217?s knowledge, in definitive proxy or information statements incorporated by reference in Part\plain\cf1\f51\fs17\ql III of this Form 10-K or any amendment to this Form 10-K.\~\~\plain\cf1\f53\fs17\ql \par\pard\plain\sb66\fi528\cf1\f51\fs17\ql Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company\plain\cf1\f51\fs17\ql or an emerging growth company. See the definitions of \u8220?large accelerated filer,\u8221? \u8220?accelerated filer,\u8221? \u8220?smaller reporting\plain\cf1\f51\fs17\ql company,\u8221? and \u8220?emerging growth company\u8221? in Rule 12b-2 of the Exchange Act.:\par\pard\plain\cf1\f51\fs6\ql \~
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs17\ql Emerging growth company\cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\cf1\f53\fs17\ql \cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell\pard\plain\intbl\cf1\f51\fs17\ql \~\cell{
{\trowd\clvertalb\cellx2204\clvertalb\cellx2356\clvertalb\cellx8016\clvertalb\cellx8168\clvertalb\cellx10480\clvertalb\cellx10632\clvertalb\cellx10800\trrh210\row}}}\pard\plain\cf1\f51\fs6\ql \~\par\pard\plain\sb66\fi528\cf1\f51\fs17\ql If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying\plain\cf1\f51\fs17\ql with any new or revised financial accounting standards provided pursuant to Section\~13(a) of the Exchange Act\~\plain\cf1\f53\fs17\ql \par\pard\plain\sb66\fi528\cf1\f51\fs17\ql Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act.)\~\~\~\~Yes\~\plain\cf1\f53\fs17\ql \plain\cf1\f51\fs17\ql \~\~\~\~No\~\plain\cf1\f53\fs17\ql \par\pard\plain\sb66\fi528\cf1\f51\fs17\ql As of June 30, 2018, the last day of the registrant\u8217?s most recently completed second fiscal quarter, the aggregate market value of the\plain\cf1\f51\fs17\ql Common Stock held by non-affiliates of the registrant was approximately $90.4 million based on the closing price of the registrant\u8217?s common\plain\cf1\f51\fs17\ql stock on June 30, 2018.\~\~The calculation excludes shares of the registrant\u8217?s common stock held by current executive officers, directors and\plain\cf1\f51\fs17\ql stockholders that the registrant has concluded are affiliates of the registrant.\~\~This determination of affiliate status is not a determination for other\plain\cf1\f51\fs17\ql purposes.\par\pard\plain\sb66\fi528\cf1\f51\fs17\ql As of February 28, 2019, there were 38,647,892 shares of common stock outstanding.\par\pard\plain\sb66\cf1\f51\fs17\b\qc DOCUMENTS INCORPORATED BY REFERENCE\par\pard\plain\sb66\fi528\cf1\f51\fs17\ql Portions of the registrant\u8217?s definitive proxy statement for its 2018 Annual Meeting of Stockholders, which the registrant intends to file\plain\cf1\f51\fs17\ql pursuant to Regulation 14A with the Securities and Exchange Commission not later than 120 days after the registrant\u8217?s fiscal year ended\plain\cf1\f51\fs17\ql December\~31, 2018, are incorporated by reference into Part III of this Annual Report on Form 10-K.\par\pard\plain\brdrb\brdrs\sa22\cf1\f51\fs8\ql \~\par\pard\plain\cf1\f51\fs12\ql \~\par\pard\plain\cf1\f51\fs12\ql \~\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
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\pard\plain\intbl\li132\fi-132\cf1\f51\fs20\ql Item 7.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_7_managements_discussion_an" }{\*\fldrslt\cf3\f51\fs20\ql Management\u8217?s Discussion and Analysis of Financial Condition and Results of Operations}}\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 69\cell{
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\pard\plain\intbl\li132\fi-132\cf1\f51\fs20\ql Item 10.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_10_directors_executive_fice" }{\*\fldrslt\cf3\f51\fs20\ql Directors, Executive Officers and Corporate Governance}}\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 77\cell{
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\pard\plain\intbl\li132\fi-132\cf1\f51\fs20\ql Item 11.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_11_executive_compensation_1" }{\*\fldrslt\cf3\f51\fs20\ql Executive Compensation}}\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 77\cell{
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\pard\plain\intbl\li132\fi-132\cf1\f51\fs20\ql Item 12.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_12_security_ownership_certa" }{\*\fldrslt\cf3\f51\fs20\ql Security Ownership of Certain Beneficial Owners and Management and Related Stockholder}}\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_12_security_ownership_certa" }{\*\fldrslt\cf3\f51\fs20\ql Matters}}\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 77\cell{
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\pard\plain\intbl\li132\fi-132\cf1\f51\fs20\ql Item 13.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_13_certain_relationships_re" }{\*\fldrslt\cf3\f51\fs20\ql Certain Relationships and Related Transactions, and Director Independence}}\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 77\cell{
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\pard\plain\intbl\li132\fi-132\cf1\f51\fs20\ql Item 14.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_14_principal_accountant_fee" }{\*\fldrslt\cf3\f51\fs20\ql Principal Accountant Fees and Services}}\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 77\cell{
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\pard\plain\intbl\li132\fi-132\cf1\f51\fs20\ql Item 15.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_15_exhibits_financial_state" }{\*\fldrslt\cf3\f51\fs20\ql Exhibits and Financial Statement Schedules}}\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 78\cell{
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\pard\plain\intbl\li132\fi-132\cf1\f51\fs20\ql Item 16.\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\ul{\field{\*\fldinst HYPERLINK \\l "item_16_form_10k_summary_1276539" }{\*\fldrslt\cf3\f51\fs20\ql Form 10-K Summary}}\cell\pard\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\qr 80\cell{
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\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\cf1\f51\fs24\ql \~{\*\bkmkstart special_note_regarding_forwardlo}{\*\bkmkend special_note_regarding_forwardlo}\par\pard\plain\cf1\f51\fs20\b\qj SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj This Annual Report on Form 10-K contains forward-looking statements within the meaning of Section\~27A of the\plain\cf1\f51\fs20\qj Securities Act of 1933, as amended, and Section\~21E of the Securities Exchange Act of 1934, as amended. All statements other\plain\cf1\f51\fs20\qj than statements of historical fact are \u8220?forward-looking statements\u8221? for purposes of this Annual Report on Form\plain\cf1\f51\fs20\qj 10-K. In some cases, you can identify forward-looking statements by terminology such as \u8220?anticipate,\u8221?\plain\cf1\f51\fs20\qj \u8220?believe,\u8221? \u8220?could,\u8221? \u8220?estimate,\u8221? \u8220?expects,\u8221? \u8220?intend,\u8221?\plain\cf1\f51\fs20\qj \u8220?may,\u8221? \u8220?plan,\u8221? \u8220?potential,\u8221? \u8220?predict,\u8221? \u8220?project,\u8221?\plain\cf1\f51\fs20\qj \u8220?should,\u8221? \u8220?will,\u8221? \u8220?would\u8221? or the negative or plural of those terms, and similar\plain\cf1\f51\fs20\qj expressions.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Forward-looking statements include, but are not limited to, statements about:
\par\pard\plain
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj our ability to fund our working capital requirements;\cell{
{\trowd\cellx972\cellx1656\cellx10800\trrh382\row}}}
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{\trowd\cellx972\cellx1656\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj the implementation of our business model and strategic plans for our business and drug candidates;\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj developments or disputes concerning our intellectual property or other proprietary rights;\cell{
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{\trowd\cellx972\cellx1656\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj our ability to maintain and establish collaborations or obtain additional funding;\cell{
{\trowd\cellx972\cellx1656\cellx10800\trrh382\row}}}
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{\trowd\cellx972\cellx1656\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj our expectations regarding government and third-party payor coverage and reimbursement;\cell{
{\trowd\cellx972\cellx1656\cellx10800\trrh382\row}}}
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{\trowd\cellx972\cellx1656\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj our ability to compete in the markets we serve;\cell{
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{\trowd\cellx972\cellx1656\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj the impact of government laws and regulations;\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj developments relating to our competitors and our industry; and\cell{
{\trowd\cellx972\cellx1656\cellx10800\trrh382\row}}}
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj the factors that may impact our financial results.\cell{
{\trowd\cellx972\cellx1656\cellx10800\trrh382\row}}}\pard\plain\sb220\fi528\cf1\f51\fs20\qj Factors that may cause actual results to differ materially from current expectations include, among other things, those set\plain\cf1\f51\fs20\qj forth in Part I, Item\~1A, \u8220?Risk Factors,\u8221? herein and for the reasons described elsewhere in this Annual Report on\plain\cf1\f51\fs20\qj Form 10-K. Any forward-looking statement in this Annual Report on Form 10-K reflects our current view with respect to future\plain\cf1\f51\fs20\qj events and is subject to these and other risks, uncertainties and assumptions relating to our operations, results of operations,\plain\cf1\f51\fs20\qj industry and future growth. Given these uncertainties, you should not rely on these forward-looking statements as predictions of\plain\cf1\f51\fs20\qj future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot\plain\cf1\f51\fs20\qj guarantee future results, levels of activity, performance or achievements. Except as required by law, we assume no obligation to\plain\cf1\f51\fs20\qj update or revise these forward-looking statements for any reason, even if new information becomes available in the future.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj This Annual Report on Form 10-K also contains estimates, projections and other information concerning our industry, our\plain\cf1\f51\fs20\qj business and the markets for certain drugs and consumer products, including data regarding the estimated size of those markets,\plain\cf1\f51\fs20\qj their projected growth rates and the incidence of certain medical conditions. Information that is based on estimates, forecasts,\plain\cf1\f51\fs20\qj projections or similar methodologies is inherently subject to uncertainties and actual events or circumstances may differ materially\plain\cf1\f51\fs20\qj from events and circumstances reflected in this information. Unless otherwise expressly stated, we obtained these industry,\plain\cf1\f51\fs20\qj business, market and other data from reports, research surveys, studies and similar data prepared by third parties, industry,\plain\cf1\f51\fs20\qj medical and general publications, government data and similar sources and we have not independently verified the data from\plain\cf1\f51\fs20\qj third party sources. In some cases, we do not expressly refer to the sources from which these data are derived.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In this Annual Report on Form 10-K, unless otherwise stated or as the context otherwise requires, references to\plain\cf1\f51\fs20\qj \u8220?Ovid,\u8221? \u8220?the Company,\u8221? \u8220?we,\u8221? \u8220?us,\u8221? \u8220?our\u8221? and similar\plain\cf1\f51\fs20\qj references refer to Ovid Therapeutics Inc. and its wholly owned subsidiaries. This Annual Report on Form 10-K also contains\plain\cf1\f51\fs20\qj references to our trademarks and to trademarks belonging to other entities. Solely for convenience, trademarks and trade names\plain\cf1\f51\fs20\qj referred to, including logos, artwork and other visual displays, may appear without the \u174? or TM symbols, but such\plain\cf1\f51\fs20\qj references are not intended to indicate, in any way, that their respective owners will not assert, to the fullest extent under\plain\cf1\f51\fs20\qj applicable law, their rights thereto. We do not intend our use or display of other companies\u8217? trade names or trademarks to\plain\cf1\f51\fs20\qj imply a relationship with, or endorsement or sponsorship of us by, any other companies.\par\pard\plain\cf1\f51\fs2\ql \~\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb264\cf1\f51\fs20\qc ii\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}{\*\bkmkstart part_i_12765393}{\*\bkmkend part_i_12765393}\par\pard\plain\cf1\f51\fs20\b\qj PART I{\*\bkmkstart item_1_3_2}{\*\bkmkend item_1_3_2}{\*\bkmkstart item_1_business_12765393}{\*\bkmkend item_1_business_12765393}\par\pard\plain\sb220\cf1\f51\fs20\b\qj Item\~1. BUSINESS\par\pard\plain\sb220\cf1\f51\fs20\b\qj Overview\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We are a biopharmaceutical company focused exclusively on developing impactful medicines for patients and families\plain\cf1\f51\fs20\qj living with rare neurological disorders. We believe these disorders represent an attractive area for drug development as the\plain\cf1\f51\fs20\qj understanding of the underlying biology has grown meaningfully over the last few years, yet has remained underappreciated by\plain\cf1\f51\fs20\qj the industry. Our experienced team began with a vision to integrate the biology and symptomology of rare neurological\plain\cf1\f51\fs20\qj conditions to employ innovative research and clinical strategies for the development of our drug candidates. Based on recent\plain\cf1\f51\fs20\qj scientific advances in genetics and the biological pathways of the brain, we created a proprietary map of disease-relevant\plain\cf1\f51\fs20\qj pathways and used it to identify and acquire novel compounds for the treatment of rare neurological disorders. We are executing\plain\cf1\f51\fs20\qj on our strategy by in-licensing and collaborating with leading biopharmaceutical companies and academic institutions. We are\plain\cf1\f51\fs20\qj developing a robust pipeline of clinical assets with an initial focus on neurodevelopmental disorders and developmental and\plain\cf1\f51\fs20\qj epileptic encephalopathies (\u8220?dEE\u8221?). Our most advanced candidate, OV101, has completed a Phase 2 trial in adults\plain\cf1\f51\fs20\qj and adolescents with Angelman syndrome, and met its primary end point demonstrating a favorable safety profile and was\plain\cf1\f51\fs20\qj generally well tolerated.\~\~It also demonstrated statistically significant exploratory endpoints of efficacy including those of Clinical\plain\cf1\f51\fs20\qj Global Impressions-Improvement (CGI-I), sleep parameters, and motor function.\~\~Pending U.S. Food and Drug Administration\plain\cf1\f51\fs20\qj (\u8220?FDA\u8221?) concurrence on the study protocol and supporting framework and materials, we intend to initiate a Phase 3\plain\cf1\f51\fs20\qj pivotal trial in 2019 in pediatric patients with Angelman syndrome called the NEPTUNE trial.\~\~Similarly, we have initiated an\plain\cf1\f51\fs20\qj open-label extension study for individuals with Angelman syndrome called ELARA which is currently recruiting.\~\~ELARA\plain\cf1\f51\fs20\qj enrolled its first subject in February of 2019 and is open to any subject who has previously been part of an OV101 clinical\plain\cf1\f51\fs20\qj trial.\~\~Along with our collaborator, Takeda Pharmaceutical Company Limited, or Takeda, we recently completed a Phase 1b/2a\plain\cf1\f51\fs20\qj trial of OV935 in adults with dEE.\~\~As announced on December 17, 2018, the Phase 1b/2a trial of OV935 achieved its primary\plain\cf1\f51\fs20\qj endpoint of safety and tolerability and showed OV935 was generally well tolerated and met its secondary exploratory endpoints\plain\cf1\f51\fs20\qj including a satisfactory pharmacokinetic profile and signals of efficacy. Exploratory analyses also showed the potential\plain\cf1\f51\fs20\qj applicability of using plasma 24-hydroxy cholesterol (24HC) as a serum biomarker. We have initiated an open-label extension\plain\cf1\f51\fs20\qj trial for those who have completed an OV935 clinical trial called ENDYMION and that study is currently enrolling.\~\~We have\plain\cf1\f51\fs20\qj also initiated two additional trials, ELEKTRA and ARCADE, in patients with dEE.\~\~\plain\cf10\f51\fs20\qj ELEKTRA is an international Phase 2,\plain\cf10\f51\fs20\qj multi-center, randomized, double-blind, placebo-controlled study that will evaluate the treatment of OV935 in pediatric patients,\plain\cf10\f51\fs20\qj aged 2 to 17 years, with epileptic seizures associated with Dravet syndrome or Lennox-Gastaut syndrome (LGS).\~ARCADE is a\plain\cf10\f51\fs20\qj Phase 2, multi-center, open-label, pilot study that will evaluate the treatment of OV935 in pediatric patients, aged 2 to 35 years\plain\cf10\f51\fs20\qj old, with epileptic seizures associated with CDKL5 Deficiency Disorder (CDD) or Duplication 15q (Dup15q) syndrome.\plain\cf1\f51\fs20\qj \~\~Both\plain\cf1\f51\fs20\qj ELEKTRA and ARCADE are currently enrolling patients.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Our most advanced drug candidate is OV101, which we acquired from H. Lundbeck A/S, or Lundbeck, in 2015. We\plain\cf1\f51\fs20\qj believe our development plan for OV101 highlights our ability to translate new scientific insights into drug candidates that target\plain\cf1\f51\fs20\qj an unexplored disease-relevant pathway. OV101 targets disorders characterized by diminished tonic inhibition, a neurological\plain\cf1\f51\fs20\qj signaling abnormality that has been identified as a potential central cause of the symptoms seen in a number of disorders of the\plain\cf1\f51\fs20\qj brain. This can lead to certain symptoms including, but not limited to motor deficiencies, sleep abnormalities, behavioral\plain\cf1\f51\fs20\qj manifestations and seizures. We believe modulating tonic inhibition may have a meaningful clinical impact in patients with\plain\cf1\f51\fs20\qj Angelman syndrome and Fragile X syndrome.\~\~The FDA granted orphan drug designation for OV101 for the treatment of\plain\cf1\f51\fs20\qj Angelman syndrome and for the treatment of Fragile X syndrome in September 2016 and October 2017, respectively, and the\plain\cf1\f51\fs20\qj FDA granted fast track designation for the treatment of Angelman syndrome and for the treatment of Fragile X syndrome in\plain\cf1\f51\fs20\qj December 2017 and March 2018, respectively.\~\~\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In January 2017, we entered into a collaboration with Takeda for its compound TAK-935, which we refer to as OV935.\plain\cf1\f51\fs20\qj The collaboration enables us to share equally in building upon Takeda\u8217?s discoveries, bringing together the capabilities of\plain\cf1\f51\fs20\qj both companies in development, regulatory and commercialization activities. We believe that OV935\u8217?s inhibition of the\plain\cf1\f51\fs20\qj cholesterol metabolism pathway may down regulate the excitatory signals involved in epilepsy, which may suppress seizures and\plain\cf1\f51\fs20\qj also lead to a long-term disease-modifying effect. We are initially targeting OV935 for rare epileptic encephalopathies with high\plain\cf1\f51\fs20\qj unmet medical need, including Dravet syndrome, Lennox-Gastaut syndrome, CDKL5 Deficiency Disorder, Dup15Q syndrome,\plain\cf1\f51\fs20\qj and Tuberous Sclerosis Complex. OV935 has completed four Phase 1 trials in certain epileptic encephalopathies, preliminarily\plain\cf1\f51\fs20\qj demonstrating favorable tolerability at doses that we believe may be therapeutically relevant.{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Our management team is a critical component to the execution of our overall strategy and our business model. We have\plain\cf1\f51\fs20\qj assembled a team with significant experience in translational science, drug evaluation, clinical development, regulatory affairs and\plain\cf1\f51\fs20\qj business development. We believe these capabilities will drive our ability to identify, acquire, develop and commercialize novel\plain\cf1\f51\fs20\qj compounds that have the potential to modify the devastating course of rare neurological disorders. We believe our expertise will\plain\cf1\f51\fs20\qj make us the partner of choice for leading biopharmaceutical companies or academic institutions that wish to maximize the value\plain\cf1\f51\fs20\qj of their neurology drug candidates. The members of our team have been collectively involved in the development and approval of\plain\cf1\f51\fs20\qj over 20 marketed drugs. Further, we believe that we are particularly well positioned to execute on our business development\plain\cf1\f51\fs20\qj strategy given the extensive network and breadth of expertise of our Chairman and Chief Executive Officer Dr.\~Jeremy Levin and\plain\cf1\f51\fs20\qj the other members of\par\pard\plain\sb264\cf1\f51\fs20\qc 1\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb220\cf1\f51\fs20\qj our management team. Our management team is supported by our board of directors, which has extensive experience in the\plain\cf1\f51\fs20\qj biopharmaceutical industry.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Our Focus: Rare Neurological Disorders\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Rare neurological disorders are among the most devastating in their impact on patients and their families. Patients suffering\plain\cf1\f51\fs20\qj from these disorders typically require full-time care, and yet are among the most underserved. We believe that there are at least\plain\cf1\f51\fs20\qj 100 neurodevelopmental disorders, epileptic encephalopathies and other related rare neurological disorders that we may be able to\plain\cf1\f51\fs20\qj target. These disorders are characterized by impairments and pathologies in the growth and development of the brain. Due to a\plain\cf1\f51\fs20\qj historical overwhelming preference in the drug industry to develop drugs for broader neurological indications, many of these\plain\cf1\f51\fs20\qj disorders have no approved therapies. As a result, recent scientific advancements have been overlooked, which we believe\plain\cf1\f51\fs20\qj presents us with an opportunity to pursue these indications. These reasons include:
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{\trowd\cellx432\cellx1116\cellx10800\trrh1125
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\i\qj High penetrance linking genetic defect to disorder pathology.\plain\intbl\cf1\f51\fs20\qj Rare neurological disorders that are genetic in origin\plain\intbl\cf1\f51\fs20\qj typically have a strong correlation, or penetrance, between the presence of a gene and the manifestation of the\plain\intbl\cf1\f51\fs20\qj corresponding disease pathology. As a result, we believe we can develop drug candidates that will be efficacious in\plain\intbl\cf1\f51\fs20\qj patients with a given genetic profile.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1125\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh1125
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\i\qj Predictive genetic and other models.\plain\intbl\cf1\f51\fs20\qj Recent advances in genetics enable us to employ predictive\plain\intbl\cf1\f51\fs20\i\qj in vivo\plain\intbl\cf1\f51\fs20\qj genetic\plain\intbl\cf1\f51\fs20\qj models of certain of these disorders. These models allow us to evaluate and observe a drug candidate\u8217?s\plain\intbl\cf1\f51\fs20\qj potential activity prior to initiation of clinical trials. Through these models, we believe we will be able to select the\plain\intbl\cf1\f51\fs20\qj most relevant clinical endpoints for our trials and increase the potential for clinical success.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1125\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh1125
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\i\qj Overlapping pathophysiology and symptoms.\plain\intbl\cf1\f51\fs20\qj Neurological disorders are often characterized by a number of\plain\intbl\cf1\f51\fs20\qj overlapping symptoms, such as seizures, sleep disturbances, movement deficiencies and behavioral manifestations.\plain\intbl\cf1\f51\fs20\qj We believe these commonalities will enable us to employ clinical endpoints that may be translatable from one\plain\intbl\cf1\f51\fs20\qj disorder to another, and to develop drugs that may provide a clinical benefit across multiple indications.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1125\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\i\qj Early observation of proof-of-concept.\plain\intbl\cf1\f51\fs20\qj By employing clinical endpoints that are highly relevant and are designed\plain\intbl\cf1\f51\fs20\qj to detect meaningful clinical benefits, we anticipate that many of our studies may provide early proof-of-concept in\plain\intbl\cf1\f51\fs20\qj clinical development.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\i\qj Potential ability to affect disease progression.\~\~\~\plain\intbl\cf1\f51\fs20\qj We are focusing on disorders that are typically diagnosed in early\plain\intbl\cf1\f51\fs20\qj childhood when the brain is still developing. We believe that we may be able to meaningfully address symptoms\plain\intbl\cf1\f51\fs20\qj and potentially alter the progression of disease, especially if the drug can be administered early in life.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh878\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh1372
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\i\qj Motivated and accessible patient populations.\~\~\~\plain\intbl\cf1\f51\fs20\qj We are targeting our programs for disorders with motivated and\plain\intbl\cf1\f51\fs20\qj accessible patient populations. We believe that the patients and caregivers affected by these disorders are avid users\plain\intbl\cf1\f51\fs20\qj of social media, in order to learn about and share relevant information and experiences. We use digital platforms to\plain\intbl\cf1\f51\fs20\qj efficiently identify new patients for our clinical trials, raise disease awareness and help connect the patient and\plain\intbl\cf1\f51\fs20\qj caregiver communities.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1372\row}}}\pard\plain\sb220\cf1\f51\fs20\b\qj The Ovid Strategy\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj The Ovid Strategy is to pursue drug development for rare neurological disorders in a manner that is scientifically\plain\cf1\f51\fs20\qj driven,\~patient focused and business development oriented. As we build on our understanding of these rare neurological\plain\cf1\f51\fs20\qj conditions, we gain an appreciation of the way the different molecular pathways underlying these disorders help drive the\plain\cf1\f51\fs20\qj symptoms patients suffer. This in turn allows us to transfer the knowledge gained about relevant molecular pathways and clinical\plain\cf1\f51\fs20\qj endpoints from one disorder to another, which we believe will enable us to build a scalable business model. Ovid has set out to\plain\cf1\f51\fs20\qj be a leader in this field, and by keeping our focus on neurology, it is our belief that our model offers us the potential to produce\plain\cf1\f51\fs20\qj multiple medicines in the future, and thereby succeed in our mission.\~\~\par\qc{\*\shppict{\pict\pngblip\picw334\pich209\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb264\cf1\f51\fs20\qc 2\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Scientifically Driven\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We take a scientifically driven approach to identify promising drug candidates for our pipeline. We are building our\plain\cf1\f51\fs20\qj portfolio based on the existence of clear biological rationales, including a focus on disorders that\~have, where possible, a direct\plain\cf1\f51\fs20\qj genetic linkage. We used our proprietary map to identify initial drug candidates\~across all stages of development for potential\plain\cf1\f51\fs20\qj acquisition or in-licensing. As we advance our drug candidates into the clinic, we are building on the emerging body of scientific\plain\cf1\f51\fs20\qj and clinical insights developed by us and others in the biopharmaceutical industry to target these new disease pathways of the\plain\cf1\f51\fs20\qj brain. As we evaluate data from previous and ongoing preclinical studies and clinical trials, we intend to refine our scientific\plain\cf1\f51\fs20\qj approach and apply these insights to continue to build our pipeline and operationalize our clinical trials. Currently our portfolio is\plain\cf1\f51\fs20\qj focused on inhibitory neuronal signaling pathways mediated by GABA (\u8216?GABA-ergic\u8217? paths) and excitatory\plain\cf1\f51\fs20\qj neuronal pathways mediated via glutamate signaling. (\u8216?glutamatergic\u8217? paths).\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In particular, the Ovid approach is driven by the following scientific principles:
\par\pard\plain
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj map biological pathways that are relevant for rare neurological disorders with significant unmet need;\cell{
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\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj target biological pathways for which proof-of-concept has been established via\plain\intbl\cf1\f51\fs20\i\qj in vitro\plain\intbl\cf1\f51\fs20\qj or animal models;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj focus on biological pathways that cause the pathology of the disorder and that have common symptoms that we can\plain\intbl\cf1\f51\fs20\qj target; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj identify and utilize biomarkers that can provide evidence of the activity of our drug candidates.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Patient Focused\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We are highly focused on the patient communities affected by the rare neurological disorders we are addressing. We\plain\cf1\f51\fs20\qj believe this aspect of our approach is critical, given that these disorders affect a small population of patients, but carry serious\plain\cf1\f51\fs20\qj morbidities and require extensive involvement from the patients\u8217? families, caregivers, physicians and patient advocacy\plain\cf1\f51\fs20\qj groups.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The Ovid Strategy is driven by the following patient-focused principles:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj develop close relationships with patients, caregivers, families, disease foundations and key opinion leaders, to better\plain\intbl\cf1\f51\fs20\qj understand the history of these disorders, raise awareness, identify patients and facilitate enrollment of clinical trials;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj identify clinically meaningful endpoints based on input from patients and their physicians and caregivers; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj develop digital capabilities to engage, foster and maintain close relationships with patient communities.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Business Development Oriented\par\pard\plain\sb220\fi264\cf1\f51\fs20\qj We have built a broad pipeline of potential drug candidates to treat rare neurological disorders through the in-licensing or\plain\cf1\f51\fs20\qj partnering of drug candidates. Central to the success of this process is a highly focused and disciplined business development\plain\cf1\f51\fs20\qj effort aimed at securing relevant assets in each of our selected rare neurological disorders.\par\pard\plain\sb220\fi264\cf1\f51\fs20\qj We are developing a specialized, scalable and robust infrastructure that we believe will make us a leader in rare neurological\plain\cf1\f51\fs20\qj disorders and the partner of choice for leading biopharmaceutical companies or academic institutions that wish to maximize the\plain\cf1\f51\fs20\qj value of their neurology drug candidates in these areas. This infrastructure spans across critical domains of drug development. If\plain\cf1\f51\fs20\qj and when our drug candidates are approved, we also plan to establish a highly focused commercial and distribution network\plain\cf1\f51\fs20\qj dedicated to rare neurological disorders in the United States and Europe, where we believe the patient populations and medical\plain\cf1\f51\fs20\qj specialists are sufficiently concentrated to effectively market our drug candidates.\par\pard\plain\sb220\fi264\cf1\f51\fs20\qj We believe that we are particularly well positioned to execute on our business development strategy because of the extensive\plain\cf1\f51\fs20\qj network of our Chairman and Chief Executive Officer Dr.\~Jeremy Levin and the other members of our management team, who\plain\cf1\f51\fs20\qj collectively have a track record of success in orphan drug development and evaluation.\par\pard\plain\sb264\cf1\f51\fs20\qc 3\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\cf1\f51\fs20\b\qj Our Pipeline\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The following table sets forth the status and mechanism of action of our drug candidates: Both the STARS trial for OV101\plain\cf1\f51\fs20\qj and the Oral Adult trial for OV935 have been completed.\par\qc\sb220{\*\shppict{\pict\pngblip\picw720\pich301\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\i\qj OV101\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We are developing OV101 for the treatment of Angelman syndrome and Fragile X syndrome, two neurodevelopmental\plain\cf1\f51\fs20\qj disorders that are characterized by similar symptoms due to decreased tonic inhibition, an important mechanism whereby it is\plain\cf1\f51\fs20\qj believed that the brain distinguishes signal from noise. Angelman syndrome and Fragile X syndrome have overlapping symptoms,\plain\cf1\f51\fs20\qj including sleep disorder, aberrant behavior, anxiety and cognitive or intellectual disabilities. Both of these disorders are typically\plain\cf1\f51\fs20\qj diagnosable in early childhood and require full-time care for the patients affected. In September 2016, the FDA granted orphan\plain\cf1\f51\fs20\qj drug designation for OV101 for the treatment of Angelman syndrome; in October 2017 the FDA granted orphan drug designation\plain\cf1\f51\fs20\qj for OV101 for the treatment of Fragile X syndrome; in December 2017 the FDA granted fast track designation for the treatment\plain\cf1\f51\fs20\qj of Angelman syndrome; and in March 2018, the FDA granted fast track designation for the treatment of Fragile X syndrome.\par\pard\plain\sb220\cf1\f51\fs20\i\qj Angelman Syndrome\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In July of 2018, we completed the Phase 2 STARS trial, a 12-week, double blind, placebo-controlled study in adults and\plain\cf1\f51\fs20\qj adolescents with Angelman syndrome that randomized 88 patients aged 13 to 49 years. The study achieved its primary endpoint\plain\cf1\f51\fs20\qj of safety and tolerability with a similar incidence of adverse events (\u8220?AEs\u8221?) across the OV101 and placebo\plain\cf1\f51\fs20\qj treatment arms. The investigational medicine showed a favorable safety profile and was well tolerated in adults and adolescents\plain\cf1\f51\fs20\qj with Angelman syndrome through the 12 weeks of treatment. The most common AEs reported in the trial were vomiting,\plain\cf1\f51\fs20\qj somnolence, irritability, aggression, and pyrexia. Serious adverse events (\u8220?SAEs\u8221?) of seizure were reported in two\plain\cf1\f51\fs20\qj patients with a previous history of seizures: one patient in the once-daily (\u8220?QD\u8221?) dose experienced a seizure that\plain\cf1\f51\fs20\qj was deemed unrelated to study drug; one patient experienced a seizure in the twice-daily (\u8220?BID\u8221?) dose group that\plain\cf1\f51\fs20\qj was assessed as possibly related to study drug by the investigator.\~\~At the prespecified efficacy analysis at 12 weeks of treatment,\plain\cf1\f51\fs20\qj OV101 once-daily and combined dosing groups showed a statistically significant improvement compared to placebo in the\plain\cf1\f51\fs20\qj CGI-I. CGI-I was ranked first in the prespecified hierarchy of the statistical analysis plan. Data from the full analysis indicate\plain\cf1\f51\fs20\qj that OV101 positively impacts several relevant clinical features of Angelman syndrome (global functioning, sleep, motor\plain\cf1\f51\fs20\qj disruption) and therefore support further clinical development of OV101 in Angelman syndrome.\~\~Ovid met with the FDA in\plain\cf1\f51\fs20\qj November of 2018 to discuss OV101 as part of its End of Phase 2 Meeting and based upon the discussion, we intend to initiate\plain\cf1\f51\fs20\qj NEPTUNE pending FDA\plain\cf10\f51\fs20\qj concurrence on the study protocol and supporting framework and materials\plain\cf1\f51\fs20\qj with initial enrollment\plain\cf1\f51\fs20\qj anticipated in the second half of 2019.\~\~Based on the STARS trial data, we have initiated ELARA which enrolled its first patient\plain\cf1\f51\fs20\qj in February of 2019 and is open to any subject who has previously been part of an OV101 clinical trial.\~\~\par\pard\plain\sb220\cf1\f51\fs20\i\qj Fragile X Syndrome{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In July 2018, we initiated our Phase 2 ROCKET clinical trial, a randomized, double-blind, parallel-group trial evaluating\plain\cf1\f51\fs20\qj OV101 for the treatment of adolescent and young male adults with Fragile X syndrome. The trial is currently enrolling and is\plain\cf1\f51\fs20\qj expected to enroll up to 30 males ages 13 to 22 with a confirmed diagnosis of Fragile X syndrome. The primary endpoint is\plain\cf1\f51\fs20\qj safety and tolerability of OV101 over 12 weeks of treatment in three different cohorts of either 5mg once daily, 5mg twice daily,\plain\cf1\f51\fs20\qj or 5mg three times daily. A secondary efficacy endpoint will evaluate changes in behavior during 12 weeks of treatment with\plain\cf1\f51\fs20\qj OV101 using the Activities-specific Balance Confidence Scale (ABC) that has been used in previous trials for Fragile X\plain\cf1\f51\fs20\qj syndrome. We anticipate data\par\pard\plain\sb264\cf1\f51\fs20\qc 4\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb220\cf1\f51\fs20\qj from this trial in the second half of 2019.\~\~We also initiated the SKY ROCKET study in the fourth quarter of 2018.\~\~The SKY\plain\cf1\f51\fs20\qj ROCKET study is a 12-week, non-drug study to assess the suitability of several behavioral scales in individuals with Fragile X\plain\cf1\f51\fs20\qj syndrome. The trial is an observational study designed to provide additional data on the key endpoints that are being explored in\plain\cf1\f51\fs20\qj the ROCKET trial as well as provide contextual data on the benefit offered by the standard of care. The study will enroll 10-30\plain\cf1\f51\fs20\qj males ages 5 to 30 with Fragile X syndrome, and data from SKY ROCKET is expected in the second half of 2019.\~\~\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj OV101 and Tonic Inhibition\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Tonic inhibition is a critical regulatory mechanism that allows a healthy human brain to decipher excitatory and inhibitory\plain\cf1\f51\fs20\qj neurological signals correctly without being overloaded. Defects of this system are thought to play a role in multiple disease\plain\cf1\f51\fs20\qj states, including Angelman syndrome and Fragile X syndrome. Because of its unique mode of action, OV101 represents a\plain\cf1\f51\fs20\qj promising compound targeting this mechanism.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Decreased tonic inhibition results in an imbalance in the ratio of excitation to inhibition. If tonic inhibition is reduced, the\plain\cf1\f51\fs20\qj brain becomes inundated with signals and loses the ability to separate background noise from critical information. This imbalance\plain\cf1\f51\fs20\qj disrupts normal brain functioning, including sensory processing and integration. This can lead to symptoms characteristic of\plain\cf1\f51\fs20\qj neurodevelopmental disorders, including those related to behavior, learning, cognitive development, motor function, sleep\plain\cf1\f51\fs20\qj disturbances and seizures. By modulating tonic inhibition, OV101 may have the potential to alleviate important symptoms and\plain\cf1\f51\fs20\qj provide a meaningful clinical benefit to patients across several neurodevelopmental disorders including Angelman syndrome and\plain\cf1\f51\fs20\qj Fragile X syndrome.\par\pard\plain\sb220\cf1\f51\fs20\b\i\qj Tonic Inhibition and Neurodevelopmental Disorders\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Neurotransmission\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The brain is composed of a vast network of interconnected neurons that facilitate the communication between cells. These\plain\cf1\f51\fs20\qj communications are governed by the release of chemical signals, or neurotransmitters, from one neuron to another. The neuron\plain\cf1\f51\fs20\qj that releases the neurotransmitter is called the presynaptic neuron. The neuron that receives the neurotransmitter is called the\plain\cf1\f51\fs20\qj postsynaptic neuron. The presynaptic neuron releases a neurotransmitter into a physical gap separating the two neurons, which is\plain\cf1\f51\fs20\qj called the synaptic gap. The neurotransmitter then diffuses across the synaptic gap to bind to a receptor on the postsynaptic\plain\cf1\f51\fs20\qj neuron. This binding then triggers a signal to stimulate, inhibit or otherwise modulate the activity of the postsynaptic neuron. For\plain\cf1\f51\fs20\qj example, gamma-aminobutyric acid, or GABA, is an inhibitory neurotransmitter that plays a role in anxiety, sleep, seizure, motor\plain\cf1\f51\fs20\qj functions and certain other brain functions. The neurotransmitter GABA binds to receptors in the synaptic gap, called synaptic\plain\cf1\f51\fs20\qj receptors, as well as receptors outside the synaptic gap, called extrasynaptic GABA receptors. The following figure depicts the\plain\cf1\f51\fs20\qj synaptic gap and extrasynaptic GABA receptors outside the synaptic gap:\par\qc\sb220{\*\shppict{\pict\pngblip\picw533\pich326\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\qj Figure 1: The neurotransmitter GABA binds to synaptic receptors in the synaptic gap and extrasynaptic GABA\par\pard\plain\cf1\f51\fs20\b\qj receptors outside the synaptic gap.\par\pard\plain\sb264\cf1\f51\fs20\qc 5\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj The Role of GABA in Phasic and Tonic Inhibition\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj There is a fine balance between an appropriate and an inappropriate response of the postsynaptic neuron to an incoming\plain\cf1\f51\fs20\qj stimulus. Neurons are typically responsive to incoming stimulus at two levels through processes known as phasic and tonic\plain\cf1\f51\fs20\qj inhibition.\par\pard\plain\sb220\fi528\cf1\f51\fs20\i\qj Phasic Inhibition.\~\~\~\~\plain\cf1\f51\fs20\qj Phasic inhibition is short-acting in nature and takes place in the synaptic gap. The brain processes\plain\cf1\f51\fs20\qj signals passed between neurons in milliseconds. To keep the system in balance, the body sets up a feedback loop so that\plain\cf1\f51\fs20\qj signaling is interpreted appropriately. When the body determines that it should cease responding to a specific signal, it triggers\plain\cf1\f51\fs20\qj this feedback loop, which inhibits the receiving neuron from responding too strongly. This is done when the neurotransmitter\plain\cf1\f51\fs20\qj GABA binds to receptors in the synaptic gap, or synaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors. Once the receiving postsynaptic neuron has been\plain\cf1\f51\fs20\qj inhibited, balance can be restored and the receiving neuron can prepare to receive a new stimulus.\par\pard\plain\sb220\fi528\cf1\f51\fs20\i\qj Tonic Inhibition.\plain\cf1\f51\fs20\qj \~\~\~\~Tonic inhibition is longer-acting in nature and takes place in the extrasynaptic region. Extrasynaptic\plain\cf1\f51\fs20\qj GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors contain specific subunits that make them different from synaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors in structure and activity.\plain\cf1\f51\fs20\qj In particular, many extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors contain a specific domain called the \u948? (delta) subunit, which is not\plain\cf1\f51\fs20\qj expressed in synaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors. These extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors that contain the \u948? subunit receptors act\plain\cf1\f51\fs20\qj with slower kinetics, hence the longer-acting inhibitory response of tonic inhibition. The following figure depicts the location and\plain\cf1\f51\fs20\qj domains of the extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptor:\par\qc\sb220{\*\shppict{\pict\pngblip\picw532\pich289\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qj Figure 2: Structure and localization of the\plain\cf1\f51\fs20\qj \u948?\plain\cf1\f51\fs20\b\qj (delta) subunit contained in the extrasynaptic GABA\plain\cf1\f51\fs18\b\qj\sub A\plain\cf1\f51\fs20\b\qj receptor.\par\pard\plain\sb264\cf1\f51\fs20\qc 6\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The following figure depicts physiologic levels of phasic inhibition and tonic inhibition, the two levels of signaling between\plain\cf1\f51\fs20\qj neurons:\par\qc\sb220{\*\shppict{\pict\pngblip\picw492\pich388\picscalex74\picscaley74\bliptag-7266410497
{\*\blipuid 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\par\pard\plain\sb220\cf1\f51\fs20\b\qj Figure 3: Phasic inhibition is rapid and short-lived. Tonic inhibition is more persistent.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The same neurotransmitter, GABA, which stimulates the short-acting receptors in the synapse in the process of phasic\plain\cf1\f51\fs20\qj inhibition, also stimulates the longer-acting receptors outside the synapse in the process of tonic inhibition.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Under normal conditions there is sufficient GABA present in and around the synaptic region and both sets of receptors are\plain\cf1\f51\fs20\qj stimulated. However, in certain neurodevelopmental disorders, the overall levels of GABA are reduced. This reduction can lead to\plain\cf1\f51\fs20\qj a situation in which there is enough GABA in the synapse to maintain normal short-term signaling, but GABA outside the\plain\cf1\f51\fs20\qj synapse is insufficient to occupy the extrasynaptic receptors and maintain longer-term signaling. The decline in tonic inhibition\plain\cf1\f51\fs20\qj triggered by the shortage of extrasynaptic GABA leads to the chronic activation of the receiving postsynaptic neurons and\plain\cf1\f51\fs20\qj disruption of normal brain network activity.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Tonic inhibition is a key mechanism of neural regulation that has not yet, to our knowledge, been specifically addressed by\plain\cf1\f51\fs20\qj any approved drug. Tonic inhibition has been shown to be important in helping to discriminate important signals from the\plain\cf1\f51\fs20\qj \u8220?noise\u8221? generated by the multitude of sensory signals entering the brain. In patients with decreased tonic inhibition,\plain\cf1\f51\fs20\qj the flood of incoming signals overwhelms the ability of the brain to process them.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The clinical manifestations of decreased tonic inhibition are seen across several neurodevelopmental disorders, including\plain\cf1\f51\fs20\qj Angelman syndrome and Fragile X syndrome. When tonic inhibition is decreased, the body has trouble functioning normally in\plain\cf1\f51\fs20\qj the presence of this chronic overstimulation of neurons. The result is profound pathology that is manifested by seizures, anxiety\plain\cf1\f51\fs20\qj and disturbances in motor function, behavior, sleep, cognition, learning, memory and ability to communicate effectively.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In addition, learning and memory are closely linked to the ability of the brain to establish and maintain connections among\plain\cf1\f51\fs20\qj nerve cells. Many brain processes, including tonic inhibition, play a role in the creation and maintenance of these connections.\plain\cf1\f51\fs20\qj One of the long-term consequences of decreased tonic inhibition is the disruption of memory. The restoration of tonic inhibition\plain\cf1\f51\fs20\qj has been observed to lead to improvements in memory in adult animal models.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj OV101 and Tonic Inhibition in Angelman Syndrome and Fragile X Syndrome\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV101 is a delta selective extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptor agonist. An agonist is a chemical that binds to a receptor and\plain\cf1\f51\fs20\qj activates the receptor to produce a biological response. OV101 specifically exerts its biological activity through the \u948?\plain\cf1\f51\fs20\qj subunit of extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors. Based on the biological pathway and existing preclinical data, we anticipate\plain\cf1\f51\fs20\qj developing OV101 as an orally active selective extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj agonist to compensate for the deficit in GABA\plain\cf1\f51\fs20\qj concentrations observed in patients with certain rare neurological disorders. We believe OV101 is the only drug candidate in\plain\cf1\f51\fs20\qj development that exerts its biological activity preferentially through the \u948? subunit of extrasynaptic receptors. We are initially\plain\cf1\f51\fs20\qj developing OV101 for Angelman syndrome and Fragile X syndrome, and we believe it has the potential to address multiple\plain\cf1\f51\fs20\qj neurodevelopmental disorders characterized by decreased tonic inhibition.\par\pard\plain\sb264\cf1\f51\fs20\qc 7\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The following figure depicts how OV101 addresses tonic inhibition by restoring activity of the extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors:\par\pard\plain\cf1\f51\fs20\qj \~\par\qc\sb220{\*\shppict{\pict\pngblip\picw521\pich657\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qj Figure 4. How OV101 is designed to address tonic inhibition by restoring activity of the extrasynaptic GABA\plain\cf1\f51\fs18\b\qj\sub A\plain\cf1\f51\fs20\b\qj receptors.\plain\cf1\f51\fs20\b\qj The figures represent the synapse between a GABAergic neuron and a postsynaptic cell. The top panel shows normal\plain\cf1\f51\fs20\b\qj release and uptake of GABA with activation of both synaptic and extrasynaptic receptors resulting in normal phasic and\plain\cf1\f51\fs20\b\qj tonic inhibition. In the middle panel, an increase in GABA uptake (Angelman syndrome) or a reduction in GABA release\plain\cf1\f51\fs20\b\qj (Fragile X syndrome) leads to a reduction in extracellular concentrations of GABA, preferentially impacting extrasynaptic\plain\cf1\f51\fs20\b\qj GABA receptor signaling and resulting in reduced tonic inhibition. In the bottom panel, OV101 acts selectively on the\plain\cf1\f51\fs20\b\qj extrasynaptic GABA\plain\cf1\f51\fs18\b\qj\sub A\plain\cf1\f51\fs20\b\qj receptors restoring tonic inhibition.\par\pard\plain\sb264\cf1\f51\fs20\qc 8\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Angelman Syndrome\par\pard\plain\sb220\fi528\cf1\f51\fs20\i\qj Overview.\plain\cf1\f51\fs20\qj \~\~\~Angelman syndrome is a rare genetic disorder that is typically diagnosed in the United States after one year of\plain\cf1\f51\fs20\qj age when parents notice severe developmental delays or the child suffers seizures. Characteristic features of this disorder include\plain\cf1\f51\fs20\qj delayed development, intellectual disability, severe speech impairment, problems with movement and balance, seizures, sleep\plain\cf1\f51\fs20\qj disorders and anxiety. Individual patients with Angelman syndrome can have varied symptoms, including the inability to walk or\plain\cf1\f51\fs20\qj control motor movement, which can limit their ability to handle daily functions such as feeding, dressing or bathing. These\plain\cf1\f51\fs20\qj patients are also often hyperactive, leading to various behavioral problems. Angelman syndrome symptoms, such as poor sleeping\plain\cf1\f51\fs20\qj patterns, can lead to serious consequences, including increased frequency of seizures and exacerbation of behavioral\plain\cf1\f51\fs20\qj manifestations. Different patients with identical genetic defects can show different degrees of these symptoms. Most Angelman\plain\cf1\f51\fs20\qj syndrome patients require full-time care and are unable to live independently, which can represent a substantial emotional and\plain\cf1\f51\fs20\qj financial burden on their families. In addition, Angelman syndrome has been associated with poor parental sleep and high\plain\cf1\f51\fs20\qj parental stress.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj According to the National Organization for Rare Disorders, the approximate prevalence of Angelman syndrome is between\plain\cf1\f51\fs20\qj 1 in 12,000 and 1 in 20,000 people. There are no FDA-approved therapies for the treatment of Angelman syndrome. The current\plain\cf1\f51\fs20\qj standard of care for seizures associated with Angelman syndrome is traditional anticonvulsants, which are not designed to\plain\cf1\f51\fs20\qj modulate tonic inhibition. There is no widely accepted standard of care for other symptoms of Angelman syndrome, including\plain\cf1\f51\fs20\qj sleep disruptions, motor dysfunction and behavioral abnormalities.\par\pard\plain\sb220\fi528\cf1\f51\fs20\i\qj Tonic Inhibition and Angelman Syndrome.\plain\cf1\f51\fs20\qj \~\~\~In 1997, scientists traced the genetic causes of Angelman syndrome to\plain\cf1\f51\fs20\qj mutations and other disruptions in the\plain\cf1\f51\fs20\i\qj UBE3A\plain\cf1\f51\fs20\qj gene. The\plain\cf1\f51\fs20\i\qj UBE3A\plain\cf1\f51\fs20\qj gene encodes the UBE3A protein, which plays a central role in\plain\cf1\f51\fs20\qj protein degradation. Protein degradation is the breakdown of damaged or unnecessary proteins within the cell, which is an\plain\cf1\f51\fs20\qj important aspect of maintaining normal cellular function. The UBE3A protein triggers the attachment of a protein called ubiquitin\plain\cf1\f51\fs20\qj to other cellular proteins. These ubiquitin attachments serve as tags that mark the tagged cellular proteins for degradation.\plain\cf1\f51\fs20\qj Alterations in the\plain\cf1\f51\fs20\i\qj UBE3A\plain\cf1\f51\fs20\qj gene, and therefore the UBE3A protein, result in deficiencies in the tagging of proteins for degradation,\plain\cf1\f51\fs20\qj leading to inappropriate protein accumulation within the cell.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj One of the proteins that the UBE3A protein normally tags for degradation is GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj Transporter 1, or GAT1, a protein\plain\cf1\f51\fs20\qj that is responsible for the uptake of GABA by neurons. The disruption in the\plain\cf1\f51\fs20\i\qj UBE3A\plain\cf1\f51\fs20\qj gene results in an overabundance of GAT1,\plain\cf1\f51\fs20\qj leading to an exaggerated uptake of GABA. This results in low levels of GABA in both the synaptic and extrasynaptic regions.\plain\cf1\f51\fs20\qj The deficiency of GABA in the extrasynaptic region culminates in a decrease of tonic inhibition, triggering a chronic activation\plain\cf1\f51\fs20\qj of downstream neurons. The following figure depicts the biological pathway by which the\plain\cf1\f51\fs20\i\qj UBE3A\plain\cf1\f51\fs20\qj gene alteration present in\plain\cf1\f51\fs20\qj Angelman syndrome patients leads to decreased tonic inhibition:\par\qc\sb220{\*\shppict{\pict\pngblip\picw168\pich359\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\ql Figure 5. Linkage between\plain\cf1\f51\fs20\b\i\ql UBE3A\plain\cf1\f51\fs20\b\ql gene alteration and tonic inhibition.\par\pard\plain\sb264\cf1\f51\fs20\qc 9\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj By adding OV101, a GABA agonist, we believe it is possible to address this decreased tonic inhibition by compensating\plain\cf1\f51\fs20\qj for the low GABA levels. Once OV101 is added, the extrasynaptic receptors are activated to transport chloride, or Cl\plain\cf1\f51\fs18\qj\super -\plain\cf1\f51\fs20\qj ions,\plain\cf1\f51\fs20\qj from outside the cell into the postsynaptic neuron. Negatively charged CI\plain\cf1\f51\fs18\qj\super -\plain\cf1\f51\fs20\qj ions inside the postsynaptic neuron increase tonic\plain\cf1\f51\fs20\qj inhibition, reducing the excessive activation of downstream neurons.\par\pard\plain\sb220\fi528\cf1\f51\fs20\i\qj Preclinical Data in Angelman Syndrome.\plain\cf1\f51\fs20\qj \~\~\~In preclinical studies conducted by an independent academic group in Angelman\plain\cf1\f51\fs20\qj syndrome mouse models, OV101 was observed to increase tonic inhibition and alleviate the key motor symptoms that are also\plain\cf1\f51\fs20\qj observed in Angelman syndrome patients.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In 2012, researchers published a study in the journal\plain\cf1\f51\fs20\i\qj Science Translational Medicine\plain\cf1\f51\fs20\qj , reporting that they had created mice\plain\cf1\f51\fs20\qj that lacked a functional copy of the\plain\cf1\f51\fs20\i\qj UBE3A\plain\cf1\f51\fs20\qj gene. In these mouse models, the researchers observed several features of Angelman\plain\cf1\f51\fs20\qj syndrome, including a loss of controlled bodily movements and motor deficits. The researchers further observed that mice lacking\plain\cf1\f51\fs20\qj a functional copy of the\plain\cf1\f51\fs20\i\qj UBE3A\plain\cf1\f51\fs20\qj gene had deficiencies in tonic inhibition and that increased GABA could partially restore this\plain\cf1\f51\fs20\qj deficiency.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In this study, analysis of the activity of individual nerve cells in mice with a defective\plain\cf1\f51\fs20\i\qj UBE3A\plain\cf1\f51\fs20\qj gene demonstrated the\plain\cf1\f51\fs20\qj effects of decreased tonic inhibition. Decreased tonic inhibition resulted in excessive neuronal activity, which caused disruption of\plain\cf1\f51\fs20\qj the normal, tightly coordinated and regulated signaling within the brain. The direct addition of OV101 to these nerve cells largely\plain\cf1\f51\fs20\qj restored their activity and regional brain network activity. Based on these results, we believe that OV101 may have a similar\plain\cf1\f51\fs20\qj effect in increasing tonic inhibition in Angelman syndrome patients.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The utility of these Angelman syndrome mouse models is also demonstrated by the effects of OV101 on walking gait.\plain\cf1\f51\fs20\qj Angelman syndrome patients often have an altered walking gait where the legs are wide-spaced and feet are turned out. The\plain\cf1\f51\fs20\qj Angelman syndrome mouse models were observed to have an altered gait, involving rotation of the hind paws outward. In this\plain\cf1\f51\fs20\qj study, Angelman syndrome mouse models and normal mice were each administered OV101 and a placebo. Administration of\plain\cf1\f51\fs20\qj OV101 was observed to result in statistically significant reductions in hind paw rotation in the Angelman syndrome mice, but had\plain\cf1\f51\fs20\qj no effect in the normal mice. The following figure depicts the decrease in hind-paw rotation in the Angelman syndrome mice\plain\cf1\f51\fs20\qj administered OV101 versus those that were administered a placebo:\par\qc\sb220{\*\shppict{\pict\pngblip\picw361\pich293\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qc Figure 6: Administration of OV101 led to a reduction in the degree of hind paw rotation.
\par\pard\plain
{\trowd\cellx432\cellx10800\trrh968
\pard\plain\intbl\sb220\cf1\f51\fs20\b\qj **\cell\pard\plain\intbl\sb220\cf1\f51\fs20\b\qj A p-value of 0.05 or less represents statistical significance, meaning that there is a less than 1-in-20 likelihood that\plain\intbl\cf1\f51\fs20\b\qj the observed results occurred by chance. A p-value of 0.01 or less means that there is a less than 1-in-100 likelihood\plain\intbl\cf1\f51\fs20\b\qj that the observed results occurred by chance.\cell{
{\trowd\cellx432\cellx10800\trrh968\row}}}\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV101 administration in Angelman syndrome mouse models was also observed to result in improved overall motor and\plain\cf1\f51\fs20\qj clasping reflex function as measured by a rotarod test and tail suspension. In the rotarod test, mice are required to perch atop a\plain\cf1\f51\fs20\qj rotating cylinder and use their legs and body in a coordinated fashion in order to avoid falling off. Angelman syndrome mice that\plain\cf1\f51\fs20\qj were administered OV101 were observed to have an increased time on the rotarod versus those that were administered a placebo.\plain\cf1\f51\fs20\qj Administration of OV101 was not observed to have an effect in normal mice. The experiment showed that the increased amount\plain\cf1\f51\fs20\qj of time shown on the rotarod after treatment was statistically significant (approximately 20%, p<0.05) relative to the time spent\plain\cf1\f51\fs20\qj on the rotarod before injection. In the tail suspension test, Angelman syndrome mice showed a mild to moderate clasping reflex,\plain\cf1\f51\fs20\qj represented by forelimb clasping and flexion to the body and smaller forelimb flexion. Angelman syndrome mice treated with\plain\cf1\f51\fs20\qj OV101 showed improved clasping reflexes and significantly increased forelimb angles (p<0.01).\par\pard\plain\sb264\cf1\f51\fs20\qc 10\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Fragile X Syndrome\par\pard\plain\sb220\fi528\cf1\f51\fs20\i\qj Overview.\~\~\~\plain\cf1\f51\fs20\qj Fragile X syndrome is a genetic condition that results in intellectual disability, anxiety disorders, behavioral and\plain\cf1\f51\fs20\qj learning challenges and various physical disabilities. Patients with Fragile X syndrome exhibit autism-like symptoms, including\plain\cf1\f51\fs20\qj cognitive impairment, anxiety, mood swings, hyperactivity, attention deficit and heightened sensitivity to various stimuli, such as\plain\cf1\f51\fs20\qj sound. The severity of an individual patient\u8217?s impairment can range from mild learning disabilities to more severe\plain\cf1\f51\fs20\qj cognitive or intellectual disabilities. Fragile X syndrome is one of the most commonly inherited intellectual disability disorders.\plain\cf1\f51\fs20\qj Children with Fragile X syndrome also often have unusual sleep patterns and may have difficulty with routine activities such as\plain\cf1\f51\fs20\qj feeding and dressing. The challenges presented by Fragile X syndrome often extend beyond the patient and can lead to significant\plain\cf1\f51\fs20\qj hardships on the emotional and financial health of their families.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Fragile X syndrome is caused by mutations in the fragile X mental retardation gene, or\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene.\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj is a gene that\plain\cf1\f51\fs20\qj leads to the synthesis of the fragile X mental retardation protein, FMRP, which is needed for normal brain development. The\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene normally contains in its sequence between 5 and 44 copies of a short, repeated motif, or recurring pattern in DNA.\plain\cf1\f51\fs20\qj In Fragile X syndrome, there are more than 200 copies of this motif in the\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene, a genetic change that prevents the\plain\cf1\f51\fs20\qj synthesis of FMRP. Patients with intermediate numbers of repeats are able to make some FMRP and have milder symptoms.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj According to the National Fragile X Foundation, Fragile X syndrome affects approximately 1 in 3,600 to 4,000 males and\plain\cf1\f51\fs20\qj 1 in 4,000 to 6,000 females. The average age of diagnosis of Fragile X syndrome is approximately three years. Currently, there\plain\cf1\f51\fs20\qj are no approved therapies for the treatment of Fragile X syndrome. The current standard of care for the psychiatric challenges of\plain\cf1\f51\fs20\qj Fragile X syndrome is tailored to each patient and may include antipsychotics, antidepressants and drugs to treat attention deficit\plain\cf1\f51\fs20\qj and sleep disorders. Special education and symptomatic treatments for anxiety and irritability are often employed to lessen the\plain\cf1\f51\fs20\qj burden of illness. Fragile X syndrome patients also may experience seizures, which are treated with traditional anticonvulsants.\par\pard\plain\sb220\fi528\cf1\f51\fs20\i\qj Tonic Inhibition and Fragile X Syndrome.\plain\cf1\f51\fs20\qj \~\~Due to mutations in the\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene, patients with Fragile X syndrome have\plain\cf1\f51\fs20\qj deficiencies in the levels of FMRP, an RNA binding protein that regulates the synthesis of proteins such as the two forms of\plain\cf1\f51\fs20\qj glutamic acid decarboxylase, or GAD65 and GAD67, which we refer to together as GAD65/67. GAD65/67 are the key enzymes\plain\cf1\f51\fs20\qj required for synthesis of GABA. Knocking out the\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene results in reduced expression of GAD65/67 in mouse models. The\plain\cf1\f51\fs20\qj following figure depicts the reduced expression of GAD65/67 in mice containing a knockout of the\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene:\par\qc\sb220{\*\shppict{\pict\pngblip\picw353\pich291\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qc Figure 7: Knockout of the\plain\cf1\f51\fs20\b\i\qc FMR1\plain\cf1\f51\fs20\b\qc gene leads to reduced expression of GAD65/67 in mice.\par\pard\plain\sb264\cf1\f51\fs20\qc 11\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The reduced expression of GAD65/67 in this model results in decreased GABA production and subsequently lower\plain\cf1\f51\fs20\qj extrasynaptic levels of GABA and decreased tonic inhibition. Decreased tonic inhibition is believed to be responsible for a\plain\cf1\f51\fs20\qj number of Fragile X syndrome-related symptoms, such as behavioral and cognitive problems. The following figure depicts the\plain\cf1\f51\fs20\qj biological pathway by which an alteration in the\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene leads to decreased tonic inhibition:\par\qc\sb220{\*\shppict{\pict\pngblip\picw166\pich327\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qc Figure 8: Linkage between\plain\cf1\f51\fs20\b\i\qc FMR1\plain\cf1\f51\fs20\b\qc gene alteration and tonic inhibition.\par\pard\plain\sb220\fi528\cf1\f51\fs20\i\qj Preclinical Data in Fragile X Syndrome.\plain\cf1\f51\fs20\qj \~\~The association between the\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene and physiological changes observed in\plain\cf1\f51\fs20\qj Fragile X syndrome patients has been evaluated in preclinical studies conducted by\~an independent academic group. Mice\plain\cf1\f51\fs20\qj containing a knockout of the\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene exhibit behaviors similar to those observed in Fragile X syndrome patients, such as\plain\cf1\f51\fs20\qj hyperactivity, anxiety and increased sensitivity to sounds.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In these studies, hyperactivity in\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj -deficient mice was assessed by the distance traveled and average speed in an open\plain\cf1\f51\fs20\qj field test.\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj -deficient mice were significantly more active than normal mice. It was observed that treatment of these mice\plain\cf1\f51\fs20\qj with OV101 led to a statistically significant decrease in the distance traveled and average speed. These results were considered to\plain\cf1\f51\fs20\qj be indicative of a reduction in hyperactivity, which we believe resulted from increased tonic inhibition. The following figure\plain\cf1\f51\fs20\qj depicts the normalization of hyperactivity in mice containing a knockout of the\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene when administered OV101:\par\qc\sb220{\*\shppict{\pict\pngblip\picw534\pich265\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qj Figure 9: OV101 was observed to reduce signs of hyperactivity in mice containing a knockout of the\plain\cf1\f51\fs20\b\i\qj FMR1\plain\cf1\f51\fs20\b\qj gene.\par\pard\plain\sb264\cf1\f51\fs20\qc 12\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In these studies, OV101 partially normalized the mice\u8217?s response to startling sounds in the pre-pulse inhibition test\plain\cf1\f51\fs20\qj in which a pre-stimulus is given to suppress the startle response and improve the signal to noise ratio. Additionally, mice with a\plain\cf1\f51\fs20\qj knockout of the\plain\cf1\f51\fs20\i\qj FMR1\plain\cf1\f51\fs20\qj gene were also observed to have higher neuronal activity as compared to normal mice and a lower\plain\cf1\f51\fs20\qj threshold for action potential, or AP, generation leading to increased AP bursts, which reverted to normal levels with the\plain\cf1\f51\fs20\qj administration of OV101, as shown in the following figure:\par\qc\sb220{\*\shppict{\pict\pngblip\picw454\pich212\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qc Figure 10. OV101 was observed to reduce levels of neuronal activity in mice with a knockout of the\plain\cf1\f51\fs20\b\i\qc FMR1\plain\cf1\f51\fs20\b\qc gene.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj OV101 and its Potential Impact on Neurogenesis and on Learning and Memory\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Based on preclinical data, we believe OV101 may facilitate neurogenesis, or the creation and maturation of new neurons,\plain\cf1\f51\fs20\qj which may lead to cognitive benefits. In a preclinical study in mice conducted by an independent academic group, OV101 was\plain\cf1\f51\fs20\qj observed to promote the performance of certain memory behaviors and facilitate neurogenesis.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors contain a unique \u948? subunit, which is a specific domain on extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors that is not expressed in synaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors. OV101 mediates its pharmacological properties via the activity of\plain\cf1\f51\fs20\qj this \u948? subunit and we believe that is a key differentiating aspect of our drug. It is believed that GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptor-dependent signaling regulates memory and also facilitates the growth of neurons after birth in the brain.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Long-term administration of OV101 in normal mice, but not in mice deficient in the GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptor delta subunit, was\plain\cf1\f51\fs20\qj observed to result in significant increases in neurogenesis. These treated mice also performed better on challenges that were\plain\cf1\f51\fs20\qj dependent on long-term memory. We believe that these results in mice suggest that long-term treatment with OV101 in patients\plain\cf1\f51\fs20\qj with Angelman syndrome and Fragile X syndrome may lead to improvement in cognitive abilities.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Previous Clinical Development of OV101\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We acquired worldwide rights to OV101 from Lundbeck in March 2015. Prior to the acquisition, Lundbeck filed an\plain\cf1\f51\fs20\qj investigational new drug application, or IND, with the FDA for the treatment of insomnia. Pursuant to this IND, Lundbeck and\plain\cf1\f51\fs20\qj Merck\~& Co., Inc., or Merck, partnered to conduct several Phase 3 trials for primary insomnia between 2004 and 2007. Over the\plain\cf1\f51\fs20\qj course of the development of OV101, over 4,000 adults were administered OV101, resulting in an OV101 exposure of\plain\cf1\f51\fs20\qj approximately 950 patient years. These trials were primarily randomized, placebo-controlled short-term and long-term safety and\plain\cf1\f51\fs20\qj efficacy clinical studies, using classic sleep parameters such as total sleep time, time to sleep onset, wakefulness after sleep onset,\plain\cf1\f51\fs20\qj and number of nocturnal awakenings as clinical endpoints.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The Phase 3 program consisted of three trials: two 3-month placebo controlled trials conducted in the United States and\plain\cf1\f51\fs20\qj one 2-week trial conducted in Europe and Canada, each evaluating OV101 against placebo and the active comparator, zolpidem\plain\cf1\f51\fs20\qj (Ambien). The primary endpoints of the trials included total sleep time and time-to-sleep onset and the secondary endpoints\plain\cf1\f51\fs20\qj included number of nocturnal awakenings, wakefulness after sleep onset and daytime function. In Phase 3 trials, which were\plain\cf1\f51\fs20\qj conducted for durations of up to 12 months, OV101 was observed to have efficacy that was largely comparable to zolpidem\plain\cf1\f51\fs20\qj (Ambien) on several sleep metrics. In the first 3-month trial, a dose of 15mg of OV101 met both of the primary endpoints as\plain\cf1\f51\fs20\qj well as the secondary endpoints at week one and month three compared to placebo. In the second 3-month trial, the same dose\plain\cf1\f51\fs20\qj met only total sleep time and number of awakenings at week one, but significance was lost after adjusting for multiplicity at\plain\cf1\f51\fs20\qj month three. The 2-week trial met all primary endpoints and wakefulness after sleep onset, for 15mg of OV101 at weeks one\plain\cf1\f51\fs20\qj and two. Additionally, subjects who were administered OV101 showed no evidence of withdrawal symptoms or rebound\plain\cf1\f51\fs20\qj insomnia after discontinuation of short-term treatment, whereas transient rebound insomnia was observed in subjects receiving\plain\cf1\f51\fs20\qj zolpidem. In addition, clear differences were observed between OV101 and zolpidem from a sleep architecture perspective.\plain\cf1\f51\fs20\qj OV101 has shown consistent increases in slow wave sleep compared to zolpidem with no significant effect on stage 2 or REM\plain\cf1\f51\fs20\qj sleep in healthy adult, elderly subjects. It is believed that slow wave sleep is important for encoding long-term, fact-based\plain\cf1\f51\fs20\qj memories. Slow wave sleep has been associated with physical changes in neuronal connections.\par\pard\plain\sb264\cf1\f51\fs20\qc 13\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Safety and Tolerability\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Overall, OV101 was observed to be well-tolerated in adult patients aged 18-64 years in the Phase 2 and Phase 3 trials at\plain\cf1\f51\fs20\qj doses of 5mg to 15mg given as evening doses. Success in these previous trials does not ensure that our clinical trials in OV101\plain\cf1\f51\fs20\qj will generate the same results or otherwise provide adequate data to demonstrate the efficacy and safety of OV101. The most\plain\cf1\f51\fs20\qj common reported adverse events were headache, nausea, vomiting, somnolence and dizziness. In general, the adverse events\plain\cf1\f51\fs20\qj appeared to be dose-related. The majority of the serious adverse events observed were considered to not be related to treatment\plain\cf1\f51\fs20\qj with OV101. One SAE, fatigue, was considered by Lundbeck and Merck as probably related to OV101 treatment. Among the 9\plain\cf1\f51\fs20\qj SAEs considered by Lundbeck and Merck to be possibly related to OV101 treatment, there were three cases of fainting and one\plain\cf1\f51\fs20\qj case each of: radius fracture, abnormal QRS axis, transient ischemic attack, non-cardiac chest pain, unresponsive to stimuli and\plain\cf1\f51\fs20\qj atrial fibrillation. Across trials there were no apparent clinical trends regarding SAEs with respect to frequency, distribution\plain\cf1\f51\fs20\qj across system organ classes or preferred terms. Also, there were no apparent clinical differences versus placebo. In the Phase 3\plain\cf1\f51\fs20\qj trials at the 15mg dose, at least one SAE was observed in 1.3% of subjects at two weeks and 3 months and 3.0% of subjects at\plain\cf1\f51\fs20\qj 12 months versus 0.0% to 1.0% on placebo over the same time frame.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Consistent with the clinical development of other insomnia drugs, the FDA requested that Lundbeck and Merck conduct a\plain\cf1\f51\fs20\qj series of preclinical and clinical abuse studies as part of their development program. In preclinical studies, OV101 demonstrated\plain\cf1\f51\fs20\qj low abuse potential. In one clinical trial, the abuse potential of OV101 was investigated in doses up to 45mg in male and female\plain\cf1\f51\fs20\qj subjects with a history of hypnotic/sedative abuse and other drug abuse. Safety results showed that OV101 administered at doses\plain\cf1\f51\fs20\qj of 30mg and 45mg in women and 45mg in men was not tolerated in this population of drug abusers, contrary to previous\plain\cf1\f51\fs20\qj experience with the same doses in healthy volunteers. This indicated that a history of drug abuse decreased tolerability to OV101\plain\cf1\f51\fs20\qj in these subjects. Adverse events that were associated with a dose-dependent lack of tolerability in this trial included psychiatric,\plain\cf1\f51\fs20\qj nervous system, musculoskeletal and gastrointestinal disorders.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In 2007, following the completion of all clinical trials for OV101 in insomnia, Lundbeck and Merck discontinued the\plain\cf1\f51\fs20\qj development program for insomnia, and announced that the overall clinical profile did not support further development of OV101\plain\cf1\f51\fs20\qj for insomnia.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Clinical Development Programs\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj OV101\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV101 is a delta selective extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptor agonist. An agonist is a chemical that binds to a receptor and\plain\cf1\f51\fs20\qj activates the receptor to produce a biological response. OV101 specifically exerts its biological activity through the \u948?\plain\cf1\f51\fs20\qj subunit of extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj receptors. Based on the biological pathway and existing preclinical data, we anticipate\plain\cf1\f51\fs20\qj developing OV101 as an orally active selective extrasynaptic GABA\plain\cf1\f51\fs18\qj\sub A\plain\cf1\f51\fs20\qj agonist to compensate for the deficit in GABA\plain\cf1\f51\fs20\qj concentrations observed in patients with certain rare neurological disorders. We believe OV101 is the only drug candidate in\plain\cf1\f51\fs20\qj development that exerts its biological activity preferentially through the \u948? subunit of extrasynaptic receptors. We are initially\plain\cf1\f51\fs20\qj developing OV101 for Angelman syndrome and Fragile X syndrome, and we believe it has the potential to address multiple\plain\cf1\f51\fs20\qj neurodevelopmental disorders characterized by decreased tonic inhibition.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj OV101 in Angelman Syndrome\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Market Overview and Current Treatments\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Angelman syndrome is a severe, lifelong, rare genetic condition that presents in early childhood and results in significant\plain\cf1\f51\fs20\qj functional limitations in behaviour, motor, sleep, and cognitive functions. Prevalence in the general population is 1in 12,000 to\plain\cf1\f51\fs20\qj 20,000.\plain\cf1\f51\fs18\qj\super 1\plain\cf1\f51\fs20\qj There are currently no approved therapies in the United States or ex-US specifically for the treatment of Angelman\plain\cf1\f51\fs20\qj syndrome. No standard of care exists for Angelman syndrome, and current therapeutic options are symptomatic, suggesting a high\plain\cf1\f51\fs20\qj unmet clinical need. Given the likely high burden of Angelman syndrome, new treatments targeting the etiology of the syndrome\plain\cf1\f51\fs20\qj that result in even small improvements in features of the syndrome may be clinically meaningful for patients and their families\~\~\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Our Development of OV101 in Angelman Syndrome\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We completed our Phase 2 trial of OV101 in adults and adolescents with Angelman syndrome, which we refer to as the\plain\cf1\f51\fs20\qj STARS trial, and have completed a Phase 1 pharmacokinetic, or PK, trial in adolescents with Angelman syndrome or Fragile X\plain\cf1\f51\fs20\qj syndrome. The Phase\~1 PK data in adolescents with Angelman syndrome and Fragile X syndrome showed OV101 to be generally\plain\cf1\f51\fs20\qj safe and well tolerated and its PK profile in adolescents was similar to previous data generated in young adults.\~\~
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\pard\plain\intbl\cf1\f51\fs18\ql\super 1\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql NORD, NIH website, Genetics Home Reference and NCBI\cell{
{\trowd\cellx220\cellx10800\trrh248\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 14\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\cf1\f51\fs20\i\qj The STARS Trial\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj STARS was a 12-week, double-blind, placebo-controlled Phase 2 study. The primary endpoint of the trial was to assess\plain\cf1\f51\fs20\qj the safety and tolerability of OV101 compared to placebo. The STARS trial explored the clinical utility of OV101 on\plain\cf1\f51\fs20\qj improvements in clinical global impressions, maladaptive behavior, sleep, and gross and fine motor skills.\par\pard\plain\cf1\f51\fs20\qj \~{\*\bkmkstart _hlk519002233_12765393}{\*\bkmkend _hlk519002233_12765393}{\*\bkmkstart _hlk519190612_12765393}{\*\bkmkend _hlk519190612_12765393}{\*\bkmkstart _hlk519190620_12765393}{\*\bkmkend _hlk519190620_12765393}\par\pard\plain\fi528\cf1\f51\fs20\qj Eighty-eight patients (adults, n=66; adolescents, n=22) aged 13 to 49 years of age diagnosed with Angelman syndrome\plain\cf1\f51\fs20\qj wer\plain\cf1\f51\fs20\qj e randomized at 13 clinical trial sites in the U.S. and Israel.\plain\cf1\f51\fs20\qj The study randomized patients to one of three arms: QD dose of\plain\cf1\f51\fs20\qj OV101 at night (15mg),\plain\cf1\f51\fs20\qj BID dose of OV101 (10mg in the morning and 15mg at night), and placebo.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj Details of the trial design are provided below:\par\pard\plain\cf1\f51\fs20\qj \~\par\qc{\*\shppict{\pict\pngblip\picw503\pich107\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\i\qj Primary Endpoint: Safety and Tolerability Data\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The study met its primary endpoint of safety and tolerability given that the AEs with OV101 treatment were similar to\plain\cf1\f51\fs20\qj placebo treatment, with the majority of AEs being mild. OV101 showed a favorable risk profile and was well tolerated through\plain\cf1\f51\fs20\qj 12 weeks of treatment. Overall, the data are consistent with the favorable risk profile observed in previous insomnia trials with\plain\cf1\f51\fs20\qj OV101.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj The most common AEs reported in the trial were vomiting, somnolence, irritability, aggression, and pyrexia.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\qj Table 1: Most Frequent Adverse Events*\par\pard\plain\cf1\f51\fs20\qj \~
\par\pard\plain
{\trowd\trqc\clvertalc\cellx2526\clvertalc\cellx4093\clvertalc\cellx5734\clvertalc\cellx7375\trrh66
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\clvertalc\cellx2526\clvertalc\cellx4093\clvertalc\cellx5734\clvertalc\cellx7375\trrh66\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh512
\pard\plain\intbl\cf1\f51\fs20\b\qj Incidence\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Placebo\par\pard\plain\intbl\cf1\f51\fs20\b\qj (n=29)\cell\pard\plain\intbl\cf1\f51\fs20\b\qj OV101 QD\par\pard\plain\intbl\cf1\f51\fs20\b\qj (n=29)\cell\pard\plain\intbl\cf1\f51\fs20\b\qj OV101 BID\par\pard\plain\intbl\cf1\f51\fs20\b\qj (n=29)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh512\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Vomiting\cell\pard\plain\intbl\cf1\f51\fs20\qj 9 (31.0%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 5 (17.2%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 5 (17.2%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Somnolence\cell\pard\plain\intbl\cf1\f51\fs20\qj 5 (17.2%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 5 (17.2%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 3 (10.3%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Irritability\cell\pard\plain\intbl\cf1\f51\fs20\qj 4 (13.8%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 3 (10.3%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 5 (17.2%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Aggression\cell\pard\plain\intbl\cf1\f51\fs20\qj 5 (17.2%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 4 (13.8%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 1 (3.4%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Pyrexia\cell\pard\plain\intbl\cf1\f51\fs20\qj 2 (6.9%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 7 (24.1%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 1 (3.4%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
\par\pard\plain
{\trowd\cellx432\cellx10800\trrh472
\pard\plain\intbl\sb220\cf1\f51\fs20\i\qj *\cell\pard\plain\intbl\sb220\cf1\f51\fs20\i\qj Descriptive data\cell{
{\trowd\cellx432\cellx10800\trrh472\row}}}\pard\plain\sb220\fi528\cf1\f51\fs20\qj Events occurring in greater than 5 percent (two or more patients) compared to placebo in either treatment arm included\plain\cf1\f51\fs20\qj pyrexia, rash, seizure, enuresis and myoclonic epilepsy.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\qj Table 2: Adverse Events Occurring More Frequently in OV101 Arms vs. Placebo*\par\pard\plain\cf1\f51\fs20\qj \~
\par\pard\plain
{\trowd\trqc\clvertalc\cellx2526\clvertalc\cellx4093\clvertalc\cellx5734\clvertalc\cellx7375\trrh66
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\clvertalc\cellx2526\clvertalc\cellx4093\clvertalc\cellx5734\clvertalc\cellx7375\trrh66\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh512
\pard\plain\intbl\cf1\f51\fs20\b\qj Incidence\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Placebo\par\pard\plain\intbl\cf1\f51\fs20\b\qj (n=29)\cell\pard\plain\intbl\cf1\f51\fs20\b\qj OV101 QD\par\pard\plain\intbl\cf1\f51\fs20\b\qj (n=29)\cell\pard\plain\intbl\cf1\f51\fs20\b\qj OV101 BID\par\pard\plain\intbl\cf1\f51\fs20\b\qj (n=29)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh512\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Pyrexia\cell\pard\plain\intbl\cf1\f51\fs20\qj 2 (6.9%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 7 (24.1%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 1 (3.4%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Rash\cell\pard\plain\intbl\cf1\f51\fs20\qj 1 (3.4%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 3 (10.3%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 2 (6.9%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Seizure\cell\pard\plain\intbl\cf1\f51\fs20\qj 0\cell\pard\plain\intbl\cf1\f51\fs20\qj 2 (6.9%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 3 (10.3%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Enuresis\cell\pard\plain\intbl\cf1\f51\fs20\qj 0\cell\pard\plain\intbl\cf1\f51\fs20\qj 2 (6.9%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 1 (3.4%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Myoclonic epilepsy\cell\pard\plain\intbl\cf1\f51\fs20\qj 0\cell\pard\plain\intbl\cf1\f51\fs20\qj 1 (3.4%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 2 (6.9%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2526\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx4093\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5734\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7375\trrh264\row}}}
\par\pard\plain
{\trowd\cellx432\cellx10800\trrh472
\pard\plain\intbl\sb220\cf1\f51\fs20\i\qj *\cell\pard\plain\intbl\sb220\cf1\f51\fs20\i\qj Descriptive data\cell{
{\trowd\cellx432\cellx10800\trrh472\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj SAEs of seizure were reported in two patients: one patient in the QD dose experienced a seizure and that was deemed\plain\cf1\f51\fs20\qj unrelated to OV101; one patient experienced a seizure in the BID dose group and that was assessed as possibly related to study\plain\cf1\f51\fs20\qj drug by the investigator.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\sb264\cf1\f51\fs20\qc 15\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\fi528\cf1\f51\fs20\qj Treatment discontinuations due to AEs were low. One patient in the placebo arm discontinued compared to no patients and\plain\cf1\f51\fs20\qj three patients in the once-daily dose group and twice-daily dose group, respectively.
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj Placebo arm: one patient with irritability\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj Twice-daily arm: one patient with myoclonus; one patient with seizure, and one patient with\plain\intbl\cf1\f51\fs20\qj irritability/anxiety/sleep disorder\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\i\qj Efficacy Endpoint Data\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj At 12 weeks of treatment, the first prespecified efficacy endpoint of CGI-I demonstrated a robust and statistically\plain\cf1\f51\fs20\qj significant difference (p=0.0206; Fisher\u8217?s Exact test) between the combined OV101 treatment arms and placebo. This\plain\cf1\f51\fs20\qj reflects an improvement in two-thirds of the combined treatment groups versus one-third in placebo.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\qj Table 3: Response Based on CGI-I at Week 12; Comparison to Placebo\par\pard\plain\cf1\f51\fs20\qj \~
\par\pard\plain
{\trowd\trqc\clvertalc\cellx2784\clvertalc\cellx5800\clvertalc\cellx7734\trrh66
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\clvertalc\cellx2784\clvertalc\cellx5800\clvertalc\cellx7734\trrh66\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2784\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5800\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7734\trrh759
\pard\plain\intbl\cf1\f51\fs20\b\qj Scale\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Pooled treatment groups\par\pard\plain\intbl\cf1\f51\fs20\b\qj (10mg/15mg BID) and
\par\pard\plain\intbl\fs16\pard\plain\intbl\cf1\f51\fs20\b\qj (15mg QD)\~\~(n=57)\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Placebo\par\pard\plain\intbl\cf1\f51\fs20\b\qj (n=28)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2784\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5800\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7734\trrh759\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2784\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5800\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7734\trrh512
\pard\plain\intbl\cf1\f51\fs20\qj Absolute number of patients who\plain\intbl\cf1\f51\fs20\qj improved\cell\pard\plain\intbl\cf1\f51\fs20\qj 38 (66.7%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 11 (39.3%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2784\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5800\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7734\trrh512\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2784\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5800\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7734\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj p-value\cell\pard\plain\intbl\cf1\f51\fs20\qj 0.0206\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2784\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5800\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx7734\trrh264\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi792\cf1\f51\fs20\qj \~\par\pard\plain\fi792\cf1\f51\fs20\qj In the prespecified analysis using the Mixed Model Repeated Measures (MMRM), which evaluated each OV101\plain\cf1\f51\fs20\qj treatment arm independently against placebo, the difference in CGI-I mean score at 12 weeks was statistically significant\plain\cf1\f51\fs20\qj (p=0.0006) in the once-daily OV101 group versus placebo and also in the combined OV101 treatment group versus placebo\plain\cf1\f51\fs20\qj (p=0.0103).\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\qj Table 4: Mean CGI-I Symptoms Overall Score \u8211? by Dose Group at Week 12; Comparison to Placebo\par\pard\plain\cf1\f51\fs20\qj \~
\par\pard\plain
{\trowd\trqc\clvertalc\cellx2527\clvertalc\cellx3866\clvertalc\cellx5637\clvertalc\cellx8704\clvertalc\cellx10800\trrh66
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
{\trowd\trqc\clvertalc\cellx2527\clvertalc\cellx3866\clvertalc\cellx5637\clvertalc\cellx8704\clvertalc\cellx10800\trrh66\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2527\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx3866\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5637\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx8704\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx10800\trrh759
\pard\plain\intbl\cf1\f51\fs20\b\qj Scale**\cell\pard\plain\intbl\cf1\f51\fs20\b\qj QD dose\plain\intbl\cf1\f51\fs20\b\qj (15mg)\par\pard\plain\intbl\cf1\f51\fs20\b\qj (n=27)\cell\pard\plain\intbl\cf1\f51\fs20\b\qj BID dose\plain\intbl\cf1\f51\fs20\b\qj (10mg/15mg) (n=28)\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Pooled treatment groups\par\pard\plain\intbl\cf1\f51\fs20\b\qj (10mg/15mg BID) and
\par\pard\plain\intbl\fs16\pard\plain\intbl\cf1\f51\fs20\b\qj (15mg QD)\~\~(n=55)\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Placebo\par\pard\plain\intbl\cf1\f51\fs20\b\qj (n=27)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2527\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx3866\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5637\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx8704\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx10800\trrh759\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2527\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx3866\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5637\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx8704\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx10800\trrh512
\pard\plain\intbl\cf1\f51\fs20\qj Mean change in CGI-I score\plain\intbl\cf1\f51\fs20\qj (week 6)\cell\pard\plain\intbl\cf1\f51\fs20\qj 3.35\cell\pard\plain\intbl\cf1\f51\fs20\qj 3.54\cell\pard\plain\intbl\cf1\f51\fs20\qj 3.45\cell\pard\plain\intbl\cf1\f51\fs20\qj 3.60\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2527\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx3866\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5637\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx8704\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx10800\trrh512\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2527\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx3866\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5637\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx8704\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx10800\trrh512
\pard\plain\intbl\cf1\f51\fs20\qj Mean change in CGI-I score\plain\intbl\cf1\f51\fs20\qj (week 12)\cell\pard\plain\intbl\cf1\f51\fs20\qj 3.00\cell\pard\plain\intbl\cf1\f51\fs20\qj 3.58\cell\pard\plain\intbl\cf1\f51\fs20\qj 3.29\cell\pard\plain\intbl\cf1\f51\fs20\qj 3.79\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2527\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx3866\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5637\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx8704\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx10800\trrh512\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2527\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx3866\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5637\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx8704\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx10800\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj p-value*** at week 12\cell\pard\plain\intbl\cf1\f51\fs20\qj 0.0006\cell\pard\plain\intbl\cf1\f51\fs20\qj 0.3446\cell\pard\plain\intbl\cf1\f51\fs20\qj 0.0103\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx2527\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx3866\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5637\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx8704\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx10800\trrh264\row}}}
\par\pard\plain
{\trowd\cellx432\cellx10800\trrh720
\pard\plain\intbl\sb220\cf1\f51\fs20\i\qj ***\cell\pard\plain\intbl\sb220\cf1\f51\fs20\i\qj MMRM analysis was performed adjusting for fixed effects of visit, treatment, age (adult vs. adolescent) and visit by\plain\intbl\cf1\f51\fs20\i\qj treatment interaction.\cell{
{\trowd\cellx432\cellx10800\trrh720\row}}}\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj In a post-hoc analysis of patients who were \u8220?much\u8221? or \u8220?minimally\u8221? improved having a CGI-I\plain\cf1\f51\fs20\qj score of \u8804?3, the data suggest that younger patients who received a once-daily dose had the greatest response to OV101\plain\cf1\f51\fs20\qj compared to older age groups.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\qj Table 5: Patients Who were \u8216?Much\u8217? or \u8216?Minimally\u8217? Improved in CGI-I Score (\u8804?3)\plain\cf1\f51\fs20\b\qj (Post-hoc Analysis)\par\pard\plain\cf1\f51\fs20\qj \~
\par\pard\plain
{\trowd\trqc\clvertalc\cellx1672\clvertalc\cellx3506\clvertalc\cellx5394\trrh66
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\pard\plain\intbl\cf1\f51\fs20\b\qj Age\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Placebo\par\pard\plain\intbl\cf1\f51\fs20\b\qj n (%)\cell\pard\plain\intbl\cf1\f51\fs20\b\qj OV101 QD\par\pard\plain\intbl\cf1\f51\fs20\b\qj n (%)\cell{
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\pard\plain\intbl\cf1\f51\fs20\qj 13-17\cell\pard\plain\intbl\cf1\f51\fs20\qj 2/7 (29%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 5/6 (83%)\cell{
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\pard\plain\intbl\cf1\f51\fs20\qj 18-24\cell\pard\plain\intbl\cf1\f51\fs20\qj 7/12 (58%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 10/12 (83%)\cell{
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\pard\plain\intbl\cf1\f51\fs20\qj 25-49\cell\pard\plain\intbl\cf1\f51\fs20\qj 2/9 (22%)\cell\pard\plain\intbl\cf1\f51\fs20\qj 7/10 (70%)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx1672\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx3506\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\cellx5394\trrh264\row}}}\pard\plain\sb220\cf1\f51\fs20\i\qj End of Phase 2 Meeting\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We met with the FDA in November of 2018 to discuss the OV101 trial results and have determined to initiate the\plain\cf1\f51\fs20\qj NEPTUNE trial in the second half of 2019.\~\~Pending the outcome of data from this study, it is intended that the NEPTUNE trial\plain\cf1\f51\fs20\qj data together with the STARS trial data will be the core studies used to support the filing of a New Drug Application (NDA)\plain\cf1\f51\fs20\qj with the FDA.\~\~\par\pard\plain\sb220\cf1\f51\fs20\i\qj NEPTUNE{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Pending FDA\plain\cf10\f51\fs20\qj concurrence on the study protocol and supporting framework and materials\plain\cf1\f51\fs20\qj , NEPTUNE is expected to be a\plain\cf1\f51\fs20\qj single 12-week, two-arm, randomized, double-blind, placebo-controlled trial with a once daily dose of OV101 versus placebo\plain\cf1\f51\fs20\qj with an\par\pard\plain\sb264\cf1\f51\fs20\qc 16\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb220\cf1\f51\fs20\qj enrollment of approximately 60 patients aged 4 to 12 years.\~\~It is expected that the primary endpoint will be the change in the\plain\cf1\f51\fs20\qj overall CGI-I score from baseline between the OV101 and placebo arms.\~\~Enrollment initiation is expected in the second half of\plain\cf1\f51\fs20\qj 2019.\par\pard\plain\sb220\cf1\f51\fs20\i\qj ELARA\par\pard\plain\sb132\fi528\cf1\f51\fs20\qj Based on the STARS trial data, we have initiated ELARA which enrolled its first patient February of 2019 and is currently\plain\cf1\f51\fs20\qj recruiting.\~\~\par\pard\plain\sb220\cf1\f51\fs20\b\i\qj OV101 in Fragile X Syndrome\par\pard\plain\sb220\cf1\f51\fs20\i\qj Market Overview and Current Treatment\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Fragile X syndrome is an inherited form of intellectual disability which manifests as a disruption in behavior, motor, sleep\plain\cf1\f51\fs20\qj and cognitive functions, and is the most common cause of autism worldwide.\~\~Fragile X syndrome prevalence is ~1/3,600-4,000\plain\cf1\f51\fs20\qj males and ~1/4,000-6,000 females.\plain\cf1\f51\fs18\qj\super 2\plain\cf1\f51\fs20\qj \~\~Currently, there are no medicines specifically approved to treat Fragile X.\~\~However, there\plain\cf1\f51\fs20\qj are many medications to target specific symptoms such as stimulants to treat ADHD, mood stabilizers and antidepressants to treat\plain\cf1\f51\fs20\qj clinical depression and generalized anxiety disorder, and sympatholytics for hyperarousal.\~\~\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\i\qj Our Development of OV101 in Fragile X Syndrome\par\pard\plain\sb220\cf1\f51\fs20\i\qj ROCKET\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In July 2018, we initiated our Phase 2 ROCKET clinical trial, a randomized, double-blind, parallel-group trial evaluating\plain\cf1\f51\fs20\qj OV101 for the treatment of adolescent and young male adults with Fragile X syndrome. The trial is currently enrolling and is\plain\cf1\f51\fs20\qj expected to enroll up to 30 males ages 13 to 22 with a confirmed diagnosis of Fragile X syndrome. The primary endpoint is\plain\cf1\f51\fs20\qj safety and tolerability of OV101 over 12 weeks of treatment in three different cohorts of either 5mg once daily, 5mg twice daily,\plain\cf1\f51\fs20\qj or 5mg three times daily. A secondary endpoint will evaluate changes in behavior during 12 weeks of treatment with OV101\plain\cf1\f51\fs20\qj using the ABC, which has previously been used in clinical trials of Fragile X syndrome. We anticipate data from this trial in the\plain\cf1\f51\fs20\qj second half of 2019.\~\~\par\pard\plain\sb220\cf1\f51\fs20\i\qj SKY ROCKET\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We also initiated the SKY ROCKET study in the fourth quarter of 2018.\~\~The SKY ROCKET study is a 12-week,\plain\cf1\f51\fs20\qj non-drug study to assess the suitability of several behavioral scales in individuals with Fragile X syndrome. The trial is an\plain\cf1\f51\fs20\qj observational study designed to provide additional data on the key endpoints that are being explored in the ROCKET trial as well\plain\cf1\f51\fs20\qj as provide contextual data on the benefit offered by the standard of care. The study will enroll 30 males ages 5 to 30 with\plain\cf1\f51\fs20\qj Fragile X syndrome, and data from SKY ROCKET are expected in the second half of 2019.\~\~\par\pard\plain\li44\sb220\cf1\f51\fs20\b\qj OV935\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj OV935 for Epileptic Encephalopathies\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We are developing OV935 in collaboration with Takeda for the treatment of rare epileptic encephalopathies. OV935 is a\plain\cf1\f51\fs20\qj potent, highly selective inhibitor of the enzyme cholesterol 24-hydroxylase, or CH24H. We believe, if approved, OV935 has the\plain\cf1\f51\fs20\qj potential to become a first-in-class inhibitor of CH24H. CH24H is predominantly expressed in the brain, where it plays a central\plain\cf1\f51\fs20\qj role in cholesterol homeostasis. Recent literature suggests that modulation of CH24H may have an impact on over-activation of\plain\cf1\f51\fs20\qj neurotransmitter pathways that have been implicated in a number of neurological disorders, such as epilepsy.\plain\cf10\f51\fs20\qj Preclinical data\plain\cf10\f51\fs20\qj suggest that inhibition of brain CH24H indirectly reduces glutamatergic signaling via NMDA receptors and modulates glial\plain\cf10\f51\fs20\qj function and inflammation, which may impact disease pathology and epileptogenesis.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV935 has completed four Phase 1 trials demonstrating favorable tolerability at doses that are believed to be\plain\cf1\f51\fs20\qj therapeutically relevant. The Phase 1b/2a trial of OV935 in adults achieved its primary endpoint of safety and tolerability and\plain\cf1\f51\fs20\qj showed OV935 was generally well tolerated.\~\~In December 2017, the FDA granted orphan drug designation for OV935 for the\plain\cf1\f51\fs20\qj treatment of Dravet syndrome and Lennox-Gastaut syndrome. We believe that OV935 offers the possibility not only to suppress\plain\cf1\f51\fs20\qj seizures, as was observed in preclinical studies, but also to modulate the underlying biological pathways that lead to the\plain\cf1\f51\fs20\qj development of seizures. This may offer the possibility of a long-term, disease-modifying therapy.\plain\cf10\f51\fs20\qj The primary objective of the\plain\cf10\f51\fs20\qj Phase 1b/2a clinical trial was to characterize the safety and tolerability profile of OV935 in adult patients with a documented\plain\cf10\f51\fs20\qj dEE. The secondary objective was to characterize the multiple dose PK profile of OV935 in adult patients with a documented\plain\cf10\f51\fs20\qj dEE.
\par\pard\plain
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\pard\plain\intbl\cf1\f51\fs18\ql\super 2\plain\intbl\cf1\f51\fs20\ql \~\cell\pard\plain\intbl\cf1\f51\fs20\ql National Fragile X Foundation\cell{
{\trowd\cellx220\cellx10800\trrh248\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 17\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Dravet Syndrome\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Dravet syndrome is a severe form of childhood epilepsy largely genetically driven by the mutation of the\plain\cf1\f51\fs20\i\qj SCN1A\plain\cf1\f51\fs20\qj gene that\plain\cf1\f51\fs20\qj typically presents during the first year of life. Eighty percent of patients have a mutation of the\plain\cf1\f51\fs20\i\qj SCN1A-\plain\cf1\f51\fs20\qj gene. Children\plain\cf1\f51\fs20\qj experience frequent seizures, loss of muscle control, cognitive deficits and, in approximately 10% of cases, death before the age\plain\cf1\f51\fs20\qj of 12 years. Children continue to suffer from seizures and severe cognitive and developmental impairment throughout their\plain\cf1\f51\fs20\qj lifetime. While some patients may survive into adulthood, their long-term intellectual development and seizure outcomes are\plain\cf1\f51\fs20\qj typically extremely poor. The incidence of Dravet syndrome in the United States ranges from 1 in 15,700 to 1 in 20,900 births.\plain\cf1\f51\fs20\qj Patients are frequently treated with combinations of classic anti-epileptic drugs, none of which are particularly effective.\plain\cf1\f51\fs20\qj However, no drug has been approved specifically for the treatment of Dravet syndrome in the United States and only one drug,\plain\cf1\f51\fs20\qj the anticonvulsant stiripentol, has been approved in Europe.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Lennox-Gastaut Syndrome\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Lennox\plain\cf1\f51\fs20\b\qj -\plain\cf1\f51\fs20\qj Gastaut syndrome is a rare disorder that is often diagnosed between three and five years of age. Patients\plain\cf1\f51\fs20\qj diagnosed with Lennox\plain\cf1\f51\fs20\b\qj -\plain\cf1\f51\fs20\qj Gastaut syndrome experience a multitude of seizure types that are difficult to manage and have many of\plain\cf1\f51\fs20\qj the same symptomologies as other rare pediatric epilepsies. Lennox\plain\cf1\f51\fs20\b\qj -\plain\cf1\f51\fs20\qj Gastaut syndrome affects over 30,000 people in the United\plain\cf1\f51\fs20\qj States with approximately half being children under the age of 18.\~\~Some patients have de novo genetic mutations, including a\plain\cf1\f51\fs20\qj mutation of the\plain\cf1\f51\fs20\i\qj SCN2A\plain\cf1\f51\fs20\qj gene. The annual incidence of Lennox\plain\cf1\f51\fs20\b\qj -\plain\cf1\f51\fs20\qj Gastaut syndrome in childhood is estimated to be 2 per 100,000\plain\cf1\f51\fs20\qj children. It is also estimated that between 1% and 4% of childhood epilepsies are a result of Lennox\plain\cf1\f51\fs20\b\qj -\plain\cf1\f51\fs20\qj Gastaut syndrome. Only\plain\cf1\f51\fs20\qj 10% of these patients have seizures that are fully controlled by existing therapies.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj CDKL5 Deficiency Disorder\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Patients with cyclin-dependent kinase-like 5 (CDKL5) mutations present with early epilepsy. In particular, early\plain\cf1\f51\fs20\qj drug-resistant epilepsy, usually starting in the first months of life, tends to be the most common feature. Complex partial\plain\cf1\f51\fs20\qj seizures, infantile spasms, myoclonic, generalized tonic-clonic, and tonic seizures have all been reported. Stereotypic hand\plain\cf1\f51\fs20\qj movements, severe hypotonia, and impaired psychomotor development are usually associated with CDKL5 mutations and\plain\cf1\f51\fs20\qj common to the general clinical manifestations.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj 15q Duplication\~\~syndrome\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Duplications of the proximal arm of chromosome 15q11.2-q13.1 result in the genetic condition 15q Duplication syndrome\plain\cf1\f51\fs20\qj (Dup15q syndrome). Multiple genes including UBE3A from this region are implicated in the pathogenesis of autism spectrum\plain\cf1\f51\fs20\qj disorders, epilepsy, and schizophrenia. Increased expression of the UBE3A gene contributes to epilepsy in 15q Duplication\plain\cf1\f51\fs20\qj syndrome and it is thought to be the underlying cause of the autistic features of the syndrome as well. The most devastating\plain\cf1\f51\fs20\qj feature of 15q Duplication syndrome is difficult to control seizures. The most common seizure types are infantile spasm and\plain\cf1\f51\fs20\qj generalized tonic\u8211?clonic seizures followed by atonic, myoclonic, focal-onset, and tonic seizures. Poorly controlled seizures\plain\cf1\f51\fs20\qj severely impact the quality of life of both affected individuals and their caregivers. Current treatment options for 15q Duplication\plain\cf1\f51\fs20\qj syndrome-associated epilepsy are often ineffective. GABAergic promoting antiepileptics are typically ineffective while\plain\cf1\f51\fs20\qj broad-spectrum antiepileptic medications such as valproic acid and rufinamide provide some relief.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Tuberous Sclerosis Complex\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Tuberous Sclerosis Complex is a genetic disorder that causes non-malignant tumors to form in many different organs,\plain\cf1\f51\fs20\qj primarily in the brain, eyes, heart, kidney, skin and lungs and is often diagnosed in childhood. The brain and skin are the most\plain\cf1\f51\fs20\qj affected organs. Tuberous Sclerosis Complex results from a mutation in tumor suppression genes\plain\cf1\f51\fs20\i\qj TSC1\plain\cf1\f51\fs20\qj or\plain\cf1\f51\fs20\i\qj TSC2\plain\cf1\f51\fs20\qj . Most cases of\plain\cf1\f51\fs20\qj Tuberous Sclerosis Complex are caused by de novo mutations of the\plain\cf1\f51\fs20\i\qj TSC1\plain\cf1\f51\fs20\qj or\plain\cf1\f51\fs20\i\qj TSC2\plain\cf1\f51\fs20\qj genes. According to the Tuberous Sclerosis\plain\cf1\f51\fs20\qj Alliance, Tuberous Sclerosis Complex is estimated to affect approximately 50,000 patients in the United States and occurs in 1 of\plain\cf1\f51\fs20\qj 6,000 live births. The most common symptom of Tuberous Sclerosis Complex is epilepsy, which occurs in 60% to 90% of\plain\cf1\f51\fs20\qj patients, of which 70% experience seizure onset in their first year of life. Despite available therapies, a significant number of\plain\cf1\f51\fs20\qj Tuberous Sclerosis Complex patients have treatment-resistant seizures. There are significant co-morbidities associated with\plain\cf1\f51\fs20\qj Tuberous Sclerosis Complex, including cognitive impairment in 50%, autism spectrum disorders in up to 40% and\plain\cf1\f51\fs20\qj neurobehavioral disorders in over 60% of individuals with Tuberous Sclerosis Complex.\par\pard\plain\sb264\cf1\f51\fs20\qc 18\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj The Role of Cholesterol Metabolism in Epileptic Encephalopathies\par\pard\plain\cf1\f51\fs20\qj \~\par\qc\sb220{\*\shppict{\pict\pngblip\picw618\pich281\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj The brain is a cholesterol-rich organ, containing about 25% of the total cholesterol in the body. Cholesterol is an essential\plain\cf1\f51\fs20\qj component of cellular membranes, including the synaptic membranes that aid in the transmission of signals between cells.\plain\cf1\f51\fs20\qj Cholesterol is also a key component of myelin, the protective layer of lipids and proteins that serves as an insulating sheath and\plain\cf1\f51\fs20\qj facilitates electrical conduction in nerve cells.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Cholesterol in the brain is entirely synthesized and metabolized locally to maintain physiologic levels. When cholesterol is\plain\cf1\f51\fs20\qj metabolized in the brain, it is broken down to 24-hydroxycholesterol, or 24HC, by CH24H, an enzyme predominantly expressed\plain\cf1\f51\fs20\qj in the brain. Converting cholesterol to 24HC enables it to pass through the blood-brain barrier and enter into the circulatory\plain\cf1\f51\fs20\qj system, allowing it to be eliminated from the body. Since CH24H is primarily present in the brain, there is a strong correlation\plain\cf1\f51\fs20\qj between circulating blood levels and brain levels of 24HC. The levels of 24HC can therefore serve as a biomarker of CH24H\plain\cf1\f51\fs20\qj activity in the brain.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj 24HC levels can profoundly impact key signaling pathways in the brain including glutamatergic signaling, or signaling by\plain\cf1\f51\fs20\qj the neurotransmitter glutamate. In one subtype of glutamate receptors called N-Methyl-D-Aspartate, or NMDA, receptors,\plain\cf1\f51\fs20\qj elevated levels of 24HC have been shown in various cellular and tissue models to lead to increased activation of the glutamate\plain\cf1\f51\fs20\qj signaling pathway. Activation of NMDA receptors has been implicated in a number of neurological disorders, including\plain\cf1\f51\fs20\qj Alzheimer\u8217?s disease and epilepsy. As a result, modulation of cholesterol metabolism has been proposed as a potential\plain\cf1\f51\fs20\qj therapeutic approach for several neurological disorders. We believe that decreasing 24HC levels, and thereby modulating NMDA\plain\cf1\f51\fs20\qj receptor activity, represents a sound rationale for addressing the underlying biology of epileptic encephalopathies. The following\plain\cf1\f51\fs20\qj figure depicts inhibition of CH24H by OV935 and its impact on excitatory signaling in the brain.\par\qc\sb220{\*\shppict{\pict\pngblip\picw357\pich255\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qj Figure 12: Through inhibition of CH24H, OV935 is believed to reduce brain levels of 24HC, thereby reducing excitatory\plain\cf1\f51\fs20\b\qj signaling.\par\pard\plain\sb264\cf1\f51\fs20\qc 19\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The glutamatergic pathway and NMDA receptors have been the targets of a number of approved drugs. Many of these\plain\cf1\f51\fs20\qj approved drugs, including anesthetics such as ketamine, were developed as antagonists of NMDA receptors, thus blocking the\plain\cf1\f51\fs20\qj receptor. These drugs have not been used in disorders such as epilepsy, where the goal is not to entirely block the NMDA\plain\cf1\f51\fs20\qj receptor, but rather to modulate its activity. The complete blockade of the NMDA receptor with long-term use is frequently\plain\cf1\f51\fs20\qj associated with poor tolerability. In some cases, low doses of NMDA receptor antagonists have demonstrated clinical benefit\plain\cf1\f51\fs20\qj outside their prescribed use, including for treatment of neurological disorders. For example, memantine, a low affinity NMDA\plain\cf1\f51\fs20\qj receptor antagonist, has been used to treat moderate to severe Alzheimer\u8217?s disease patients because it does not completely\plain\cf1\f51\fs20\qj block the NMDA receptor. Modulation of the NMDA receptor, rather than NMDA receptor antagonism, could provide a more\plain\cf1\f51\fs20\qj effective method for treatment of neurological disorders.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj A number of publications by independent academic groups have shown that 24HC is a potent modulator of the NMDA\plain\cf1\f51\fs20\qj receptor. These publications describe 24HC as a positive allosteric modulator, a molecule that induces a conformational change\plain\cf1\f51\fs20\qj within the protein structure of the receptor and increases its activity. Mice lacking CH24H expression have reduced brain levels\plain\cf1\f51\fs20\qj of 24HC and decreased NMDA receptor signaling. Therefore reducing 24HC levels in the brain offers an alternate mechanism for\plain\cf1\f51\fs20\qj modulating NMDA receptor activity without blocking normal receptor function. We believe that reducing 24HC levels represents\plain\cf1\f51\fs20\qj an innovative approach to impacting the glutamatergic pathway to treat epileptic encephalopathies. The potential importance of\plain\cf1\f51\fs20\qj this target, along with the strength of the data supporting it, is what attracted us to OV935 as a potential treatment for these\plain\cf1\f51\fs20\qj disorders.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj OV935 Preclinical Data\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV935 has been evaluated in multiple preclinical epilepsy and seizure models. In these studies, OV935 was observed to\plain\cf1\f51\fs20\qj have anti-convulsive activity in genetic, pharmacologic and inflammation-induced seizure models.\~\~Based on the preclinical data\plain\cf1\f51\fs20\qj available to us, OV935 may have diverse effects on overall brain function, affecting both seizure intensity and frequency, and\plain\cf1\f51\fs20\qj potentially modifying the underlying disease biology. We believe the data provide a rationale to test OV935 in multiple epileptic\plain\cf1\f51\fs20\qj encephalopathies. The models are summarized as follows:\par\pard\plain\cf1\f51\fs20\qj \~
\par\pard\plain
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\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
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{\trowd\trqc\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3993\clbrdrb\brdrs\brdrcf7\clvertalb\cellx4206\clbrdrb\brdrs\brdrcf1\clvertalb\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\b\qj Model\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Observed OV935 Activity\cell{
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{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\qj SCN1A Knock-In Model of DS\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Increased temperature threshold for hyperthermia-induced seizures\cell{
{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\qj Pentylenetetrazol (PTZ) Kindling Model\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Reduced PTZ-induced seizure progression\cell{
{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\qj Fring\u8217?s Audiogenic Seizure Model\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Reduced audiogenic seizures\cell{
{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\qj APP/PS1 Transgenic Mouse Model\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Prolonged overall survival\cell{
{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248\row}}}
{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\qj TMEV Mouse Model\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Decreased seizure activity and duration\cell{
{\trowd\trqc\clvertalb\cellx3993\clvertalb\cellx4206\clvertalb\cellx10800\trrh248\row}}}\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj SCN1A Knock-In Model of Dravet Syndrome\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV935 was tested in a knock-in model of Dravet syndrome constructed by inactivation of the\plain\cf1\f51\fs20\i\qj SCN1A\plain\cf1\f51\fs20\qj gene. This gene\plain\cf1\f51\fs20\qj encodes a voltage-gated sodium channel that plays a critical role in the normal functioning of inhibitory pathways in the brain.\plain\cf1\f51\fs20\qj Deficiencies in the functioning of this channel allow brain excitatory pathways to function unchecked, resulting in severe\plain\cf1\f51\fs20\qj seizures. The majority of Dravet syndrome cases are caused by mutations in this gene. Mice containing the\plain\cf1\f51\fs20\i\qj SCN1A\plain\cf1\f51\fs20\qj gene mutation\plain\cf1\f51\fs20\qj have hyperthermia-induced or high-temperature-induced seizures. Mice treated with OV935 were observed to have a\plain\cf1\f51\fs20\qj significantly raised threshold temperature for developing these seizures after seven days of dosing, relative to untreated mice, as\plain\cf1\f51\fs20\qj depicted below.\par\pard\plain\cf1\f51\fs20\qj \~\par\qc{\*\shppict{\pict\pngblip\picw474\pich262\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\i\qc Source: RIKEN Brain Science Institute, Neurogenetics laboratory (Lab head; Kazuhiro Yamakawa).\par\pard\plain\sb220\cf1\f51\fs20\b\qc Figure 13: OV935 increases the threshold for temperature-induced seizures in mice containing the\plain\cf1\f51\fs20\b\i\qc SCN1A\plain\cf1\f51\fs20\b\qc gene mutation.\par\pard\plain\sb264\cf1\f51\fs20\qc 20\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj PTZ Kindling Model\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV935 was tested in a preclinical kindling seizure model. Scientists use kindling models to study the effects of repeat\plain\cf1\f51\fs20\qj seizures in the brain. One such kindling model described here is the pentylenetetrazol, or PTZ, model. As depicted in the figure\plain\cf1\f51\fs20\qj below, it has been observed that repeat stimulation can increase the likelihood of seizures, presumably because there is a\plain\cf1\f51\fs20\qj threshold for seizures to occur and the repeat stimulation lowers this threshold. In this model, PTZ is used to chemically\plain\cf1\f51\fs20\qj stimulate mice at sub-convulsive levels. PTZ also increases the density and sensitivity of glutamate receptors in specific regions\plain\cf1\f51\fs20\qj of the brain. Mice that were dosed daily with OV935 demonstrated a significant delay in seizure development in this model.\par\qc\sb220{\*\shppict{\pict\pngblip\picw305\pich209\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qc Figure 14: OV935 delayed seizure development in the PTZ-induced kindling mouse model.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Fring\u8217?s Audiogenic Seizure Model\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV935 was tested in a preclinical audiogenic seizure model. The Fring\u8217?s audiogenic seizure model is widely used\plain\cf1\f51\fs20\qj by scientists to investigate the effects of investigational drugs in a model sensitive to sound-induced seizures. In the experiment,\plain\cf1\f51\fs20\qj OV935 was dosed once a day for either one or three days. The effect of OV935 on the duration of seizures was determined after\plain\cf1\f51\fs20\qj the induction of a seizure either one hour or 24 hours following administration of the last dose. As depicted in the figure below,\plain\cf1\f51\fs20\qj it was observed that OV935 treatment resulted in a significant dose-dependent reduction in sound-induced seizures following\plain\cf1\f51\fs20\qj single and 3-day repeat dosing.\par\qc\sb220{\*\shppict{\pict\pngblip\picw510\pich375\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb110\cf1\f51\fs20\b\qc Figure 15: OV935 dose-dependently reduced seizure in the Fring\u8217?s audiogenic seizure model.\par\pard\plain\cf1\f51\fs20\qc 90\plain\cf1\f51\fs20\b\i\qc APP/PS1 Transgenic Mouse Model\par\pard\plain\sb264\cf1\f51\fs20\qc 21\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV935 was tested in a preclinical Alzheimer\u8217?s disease model where an amyloid precursor protein, or APP,\plain\cf1\f51\fs20\qj overexpressing mouse was crossed with a presenilin-1, or PS1, mutant mouse that is highly prone to developing spontaneous\plain\cf1\f51\fs20\qj seizures. We believe that results obtained in this model yield some valuable insights into neurological disorders, and particularly\plain\cf1\f51\fs20\qj into the biochemistry of the brain. Mice in this model typically have a high incidence of sudden death with only 50% of them\plain\cf1\f51\fs20\qj surviving after three months. As depicted in the figure below, mice treated with OV935 in this model were observed to have a\plain\cf1\f51\fs20\qj significant increase in overall survival. While it is unclear if the increase in survival is directly related to reduction in seizures,\plain\cf1\f51\fs20\qj increase in survival has previously been observed in APP/PS1 mice when one copy of the gene for CH24H is inactivated,\plain\cf1\f51\fs20\qj suggesting that the survival benefit observed after treatment with OV935 may be due to inhibition of its intended target, CH24H.\par\qc\sb220{\*\shppict{\pict\pngblip\picw444\pich264\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\cf1\f51\fs20\b\qc Figure 16: OV935 increased survival in APP/PS1 transgenic mouse model.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj TMEV Mouse Model\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV935 was tested in a Theiler\u8217?s murine encephalomyelitis virus, or TMEV, model to determine the role of OV935\plain\cf1\f51\fs20\qj in reducing inflammation-induced seizures. Infection with TMEV in this model leads to acute seizures and significant elevations\plain\cf1\f51\fs20\qj in inflammatory signaling molecules, known as cytokines. A large fraction of the mice develop spontaneous, recurrent seizures\plain\cf1\f51\fs20\qj and various behavioral co-morbidities weeks later. As depicted below, treatment with OV935 demonstrated reduction in the\plain\cf1\f51\fs20\qj overall number and average severity of seizures in the mice in the acute phase. In addition, long-term benefits were observed,\plain\cf1\f51\fs20\qj based on significant improvements in anxiety assays such as the open field test.\par\qc\sb220{\*\shppict{\pict\pngblip\picw468\pich165\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb264\cf1\f51\fs20\b\qc Figure 17: OV935 reduced the number of seizures and the number of severe (Stage 4/5) seizures in the\par\pard\plain\cf1\f51\fs20\b\qc TMEV model.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj OV935 Clinical Data\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj OV935 has been tested in 86 healthy volunteers across four Phase 1 trials. Single oral doses of up to 1,350mg of OV935\plain\cf1\f51\fs20\qj were well-tolerated. The most frequently reported adverse events were headache, ECG electrode application site dermatitis and\plain\cf1\f51\fs20\qj nausea. All reported events were mild with no apparent dose-response. In a 14-day repeat dosing trial, doses of 100mg QD,\plain\cf1\f51\fs20\qj 300mg QD and 400mg QD were well-tolerated. One volunteer at the 300mg BID experienced an event of confusional state and\plain\cf1\f51\fs20\qj another volunteer at the 600mg QD dose experienced acute psychosis. Both volunteers discontinued the trial at day 11. One\plain\cf1\f51\fs20\qj volunteer receiving placebo reported events of nightmares, spatial disorientation, insomnia and dizziness. All AEs resolved with\plain\cf1\f51\fs20\qj continued dosing through day 15. No SAEs were reported. Overall, no safety issues of concern were identified in the Phase\~1\plain\cf1\f51\fs20\qj trials based on assessments of physical examinations, vital sign measurements, clinical laboratory values or 12-lead\plain\cf1\f51\fs20\qj electrocardiogram findings.\par\pard\plain\sb264\cf1\f51\fs20\qc 22\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The following table summarizes each trial:\par\pard\plain\cf1\f51\fs20\qj \~
\par\pard\plain
{\trowd\clbrdrb\brdrs\brdrcf7\clvertalb\cellx546\clbrdrb\brdrs\brdrcf7\clvertalb\cellx768\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3906\clbrdrb\brdrs\brdrcf7\clvertalb\cellx4128\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7374\clbrdrb\brdrs\brdrcf7\clvertalb\cellx7596\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8682\clbrdrb\brdrs\brdrcf7\clvertalb\cellx8904\clbrdrb\brdrs\brdrcf1\clvertalb\cellx10800\trrh495
\pard\plain\intbl\brdrb\brdrs\cf1\f51\fs20\b\qj Trial\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Purpose\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Design\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Number of\par\pard\plain\intbl\cf1\f51\fs20\b\qj Volunteers\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Dosage\cell{
{\trowd\clbrdrb\brdrs\brdrcf7\clvertalb\cellx546\clbrdrb\brdrs\brdrcf7\clvertalb\cellx768\clbrdrb\brdrs\brdrcf1\clvertalb\cellx3906\clbrdrb\brdrs\brdrcf7\clvertalb\cellx4128\clbrdrb\brdrs\brdrcf1\clvertalb\cellx7374\clbrdrb\brdrs\brdrcf7\clvertalb\cellx7596\clbrdrb\brdrs\brdrcf1\clvertalb\cellx8682\clbrdrb\brdrs\brdrcf7\clvertalb\cellx8904\clbrdrb\brdrs\brdrcf1\clvertalb\cellx10800\trrh495\row}}}
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh742
\pard\plain\intbl\cf1\f51\fs20\qj 1\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Safety and tolerability\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Phase 1, randomized, double-blind,\plain\intbl\cf1\f51\fs20\qj placebo-controlled, single ascending\plain\intbl\cf1\f51\fs20\qj dose trial\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj 48\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj 15-1,350mg, oral\cell{
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh742\row}}}
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell{
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh248\row}}}
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh742
\pard\plain\intbl\cf1\f51\fs20\qj 2\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Safety and tolerability\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Phase 1, randomized, double-blind,\plain\intbl\cf1\f51\fs20\qj placebo-controlled, multiple ascending\plain\intbl\cf1\f51\fs20\qj dose trial\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj 40\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj 100-600mg\~QD,\plain\intbl\cf1\f51\fs20\qj and\~300mg\~BID,\plain\intbl\cf1\f51\fs20\qj 14\~days, oral\cell{
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh742\row}}}
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell{
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh248\row}}}
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh742
\pard\plain\intbl\cf1\f51\fs20\qj 3\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Brain CH24H enzyme occupancy\plain\intbl\cf1\f51\fs20\qj using positron emission tomography,\plain\intbl\cf1\f51\fs20\qj or PET\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Open-label, non-randomized\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj 11\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj 50-600mg, oral\cell{
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh742\row}}}
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh248
\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\cell{
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh248\row}}}
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh742
\pard\plain\intbl\cf1\f51\fs20\qj 4\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Relative bioavailability of tablet\plain\intbl\cf1\f51\fs20\qj versus solution formulation; effect of\plain\intbl\cf1\f51\fs20\qj food\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj Phase 1, randomized, open-label,\plain\intbl\cf1\f51\fs20\qj single dose trial\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj 9\cell\pard\plain\intbl\cf1\f51\fs20\qj \~\~\cell\pard\plain\intbl\cf1\f51\fs20\qj 300mg\~(tablet),\~oral;\plain\intbl\cf1\f51\fs20\qj 300mg\~(solution),\~oral\cell{
{\trowd\cellx546\clvertalb\cellx768\cellx3906\clvertalb\cellx4128\cellx7374\clvertalb\cellx7596\cellx8682\clvertalb\cellx8904\cellx10800\trrh742\row}}}\pard\plain\sb220\fi528\cf1\f51\fs20\qj In the Phase 1 PET imaging trial, following administration of OV935, levels of plasma 24HC decreased as the dose\plain\cf1\f51\fs20\qj increased, reaching an apparent plateau of a 60% reduction at a dose of 300mg, as depicted in the figure below.\par\qc\sb220{\*\shppict{\pict\pngblip\picw446\pich257\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb220\cf1\f51\fs20\b\qc Figure 18: Dose-dependent reduction in plasma 24HC by OV935 in a Phase 1 multiple ascending-dose trial.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj OV935 Clinical Development Plan\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Phase 1b/2a Trial\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The Phase 1b/2a trial of OV935 achieved its primary endpoint of safety and tolerability and showed OV935 was generally\plain\cf1\f51\fs20\qj well tolerated.\~\~\plain\cf10\f51\fs20\qj The trial was designed to have two parts. Part 1 was a randomized, double-blind, placebo-controlled (OV935 vs.\plain\cf10\f51\fs20\qj placebo with a ratio of 4:1), 30-day phase that included a titration period (20 days: 100 mg, 200 mg twice daily), and treatment\plain\cf10\f51\fs20\qj period (10 days).\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj Details of the trial design are provided below:\par\qc\sb220{\*\shppict{\pict\pngblip\picw524\pich144\picscalex74\picscaley74\bliptag-7266410497
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\par\pard\plain\sb264\cf1\f51\fs20\qc 23\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf10\f51\fs20\qj The target final dose of 300 mg BID could be reached after the 20-day titration period. Part 2 was a 60-day open-label\plain\cf10\f51\fs20\qj phase to explore the extent to which OV935 reduces seizure frequency as well as longer-term safety, tolerability, PK, and\plain\cf10\f51\fs20\qj 24HC\~plasma levels. Patients who rolled over to Part 2 started OV935 at 200 mg BID for 10 days (second titration period) and\plain\cf10\f51\fs20\qj increased to 300 mg BID until Day 85 followed by down titration to Day 92 (end of treatment period). Patients received OV935\plain\cf10\f51\fs20\qj or placebo in addition to their standard antiepileptic treatment regimens.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\i\qj Primary Endpoint: Safety and Tolerability Results\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj OV935 achieved the primary endpoint of safety and tolerability as measured by incidence of AEs. AEs in patients treated\plain\cf1\f51\fs20\qj with OV935 were similar to those who received placebo in Part 1. The majority of AEs in both treatment arms were mild.\plain\cf1\f51\fs20\qj Overall, the data are consistent with a favorable safety and tolerability profile and support the continued clinical development of\plain\cf1\f51\fs20\qj OV935.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj AEs that occurred more frequently in the OV935-treatment group versus the placebo group were: dysarthria, insomnia,\plain\cf1\f51\fs20\qj lethargy, seizure cluster, and upper respiratory infection. Four patients discontinued due to an AE or an SAE in the OV935\plain\cf1\f51\fs20\qj treatment arm. Of these, in Part 1, one patient discontinued due to difficulty with walking and worsening lethargy and a second\plain\cf1\f51\fs20\qj discontinued due to weakness. In Part 2, one patient discontinued due to a single episode of seizure cluster and a second\plain\cf1\f51\fs20\qj experienced multiple seizure clusters.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj An increase in seizure frequency was seen in three patients, all of whom were on perampanel. This suggests the potential\plain\cf1\f51\fs20\qj for a drug-drug interaction between medicines acting on different glutamatergic receptors. Accordingly, changes in seizure\plain\cf1\f51\fs20\qj frequency data for the Phase 1b/2a trial are now reported with the inclusion and exclusion of the three patients on perampanel,\plain\cf1\f51\fs20\qj respectively.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\i\qj Secondary and Exploratory Endpoint Results\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj PK parameters:\plain\cf1\f51\fs20\qj The data reaffirm the PK profile seen in previous studies. Specifically, plasma levels of OV935 were\plain\cf1\f51\fs20\qj dose-proportional and consistent with levels observed in four prior Phase 1 studies in healthy volunteers.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj In Part 1, a dose-dependent reduction of plasma 24HC levels was observed with OV935 treatment compared to placebo. A\plain\cf1\f51\fs20\qj similar reduction was observed in Part 2 in both the OV935-treatment arm and patients in the placebo arm who crossed over to\plain\cf1\f51\fs20\qj receive study drug. Importantly, there was an association between the reduction of 24HC and the median reduction of seizure\plain\cf1\f51\fs20\qj frequency with OV935 treatment. By end of treatment period, 12 of 14 patients had interpretable 24HC data and seizure\plain\cf1\f51\fs20\qj frequency counts. Individuals achieving plasma levels of <10 ng/ml (an approximate 80 percent decrease from baseline) at Day\plain\cf1\f51\fs20\qj 85 (n=7) showed a median seizure reduction of 69 percent compared to 3 percent for those who did not obtain this degree of\plain\cf1\f51\fs20\qj 24HC reduction (n=5). Accordingly, 24HC will be further studied as a potential biomarker in OV935 clinical trials.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj Exploratory analysis of seizure data:\plain\cf1\f51\fs20\qj Median percent reduction from baseline seizure frequency is being reported on patients\plain\cf1\f51\fs20\qj treated with OV935 during the 60-day open-label Part 2 period for all seizure types (Table 1). Based on individual patient\plain\cf1\f51\fs20\qj analysis, three patients on concomitant perampanel had increased seizure frequency during the study, consistent with a potential\plain\cf1\f51\fs20\qj drug-drug interaction, as described above. A subset analysis was conducted on 11 patients, who were not taking perampanel.\plain\cf1\f51\fs20\qj (Table 1).\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\fi528\cf1\f51\fs20\qj Overall, seizure frequency reduction was observed with maximal effect in the later part of the treatment period.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\cf1\f51\fs20\b\qj Table 1:\par\pard\plain\cf1\f51\fs20\qj \~
\par\pard\plain
{\trowd\trqc\clvertalc\cellx3770\clvertalc\cellx6232\clvertalc\cellx9349\trrh66
\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell\pard\plain\intbl\f0\fs16\ql \~\cell{
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\pard\plain\intbl\cf1\f51\fs20\b\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Median Seizure Frequency\cell{
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{\*\bkmkstart _hlk532396894_12765393}{\*\bkmkend _hlk532396894_12765393}\pard\plain\intbl\cf1\f51\fs20\b\qj \~\cell\pard\plain\intbl\cf1\f51\fs20\b\qj Full Analysis Set (FAS)\plain\intbl\cf1\f51\fs20\b\qj Part 2*\cell\pard\plain\intbl\cf1\f51\fs20\b\qj FAS Part 2 excluding patients on\plain\intbl\cf1\f51\fs20\b\qj Perampanel**\cell{
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\pard\plain\intbl\cf1\f51\fs20\b\qj Reduction from Baseline in Seizure Frequency\cell{
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{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Day 92\~(measured from Day 65-92)\cell\pard\plain\intbl\cf1\f51\fs20\qj \~45% (n=14)\cell\pard\plain\intbl\cf1\f51\fs20\qj \~61% (n=11)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Day 85 (measured from Day 58-85)\cell\pard\plain\intbl\cf1\f51\fs20\qj \~28% (n=14)\cell\pard\plain\intbl\cf1\f51\fs20\qj \~41% (n=11)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Day 69 (measured from Day 42-69)\cell\pard\plain\intbl\cf1\f51\fs20\qj \~24% (n=16)\cell\pard\plain\intbl\cf1\f51\fs20\qj \~37% (n=13)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264
\pard\plain\intbl\cf1\f51\fs20\b\qj Total Seizure Free Days\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Baseline\cell\pard\plain\intbl\cf1\f51\fs20\qj 11.7 (n=16)\cell\pard\plain\intbl\cf1\f51\fs20\qj 12.7 (n=13)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Day 92 (measured from Day 65-92)\cell\pard\plain\intbl\cf1\f51\fs20\qj 14.0 (n=14)\cell\pard\plain\intbl\cf1\f51\fs20\qj 16.8 (n=11)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264
\pard\plain\intbl\cf1\f51\fs20\b\qj Responder Analysis \u8211? Proportion of Patients with Seizure Reduction from Baseline\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Day 65-92: 100% reduction (seizure free)\cell\pard\plain\intbl\cf1\f51\fs20\qj \~14.3% (n=14)\cell\pard\plain\intbl\cf1\f51\fs20\qj 18.2% (n=11)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264\row}}}
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264
\pard\plain\intbl\cf1\f51\fs20\qj Day 65-92: \u8805?50% reduction\cell\pard\plain\intbl\cf1\f51\fs20\qj \~42.9% (n=14)\cell\pard\plain\intbl\cf1\f51\fs20\qj 54.5% (n=11)\cell{
{\trowd\trqc\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx3770\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx6232\clbrdrt\brdrs\brdrcf1\clbrdrl\brdrs\brdrcf1\clbrdrr\brdrs\brdrcf1\clbrdrb\brdrs\brdrcf1\clvertalc\cellx9349\trrh264\row}}}\pard\plain\cf1\f51\fs20\qj \~
\par\pard\plain
{\trowd\cellx432\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj *\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj FAS: 18 patients randomized to receive OV935 in Part 1 (titration period). Two withdrew from Part 1 and 16 patients rolled\plain\intbl\cf1\f51\fs20\qj over to Part 2 (treatment period); 14 patients completed the trial.\cell{
{\trowd\cellx432\cellx10800\trrh630\row}}}\pard\plain\sb264\cf1\f51\fs20\qc 24\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~
\par\pard\plain
{\trowd\cellx432\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj **\cell{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\pard\plain\intbl\sb132\cf1\f51\fs20\qj FAS Part 2 without perampanel: Excludes 3 patients taking perampanel for a total of 13 patients; 11 patients completed the\plain\intbl\cf1\f51\fs20\qj trial.\cell{
{\trowd\cellx432\cellx10800\trrh630\row}}}\pard\plain\sb220\fi528\cf10\f51\fs20\qj Exploratory analysis of OV935 showed reduction in seizure frequency that was correlated with decreases in plasma\plain\cf10\f51\fs20\qj 24-hydroxycholesterol (24HC) levels in adults across multiple dEE. OV935 is a potent, highly-selective first-in-class inhibitor\plain\cf10\f51\fs20\qj of the enzyme cholesterol 24-hydroxylase (CH24H) being investigated as a novel approach to treating epilepsy. Based on the\plain\cf10\f51\fs20\qj insights gained from the Phase 1b/2a trial, Ovid and Takeda will continue with the dose and titration schedule used in the Phase\plain\cf10\f51\fs20\qj 2 ELEKTRA and ARCADE trials of OV935 in patients ages 2 to 17 years. In addition, Ovid will amend the protocols for these\plain\cf10\f51\fs20\qj trials to exclude patients being treated with perampanel and, in light of the mode of action of OV935, the duration of treatment\plain\cf10\f51\fs20\qj will be extended with the potential to observe the extent of the effects of OV935 on seizure reduction over time.\par\pard\plain\sb220\cf1\f51\fs20\i\qj ENDYMION\par\pard\plain\sb220\fi528\cf10\f51\fs20\qj Ovid and Takeda will continue to enroll eligible patients in the ENDYMION open-label extension study.\~\~ENDYMION is\plain\cf10\f51\fs20\qj a multi-center open-label extension study of OV935 in patients with dEE who have participated in a previous OV935 clinical\plain\cf10\f51\fs20\qj study. The primary objective is to assess the long-term safety and tolerability of OV935 over two years of treatment in patients\plain\cf10\f51\fs20\qj with rare epilepsies. A secondary endpoint will evaluate the effect of OV935 on seizure frequency over two years.\~\par\pard\plain\sb220\cf10\f51\fs20\i\qj ELEKTRA\par\pard\plain\sb220\fi528\cf10\f51\fs20\qj ELEKTRA is an international Phase 2, multi-center, randomized, double-blind, placebo-controlled study that will evaluate\plain\cf10\f51\fs20\qj the treatment of OV935 in pediatric patients, aged 2 to 17 years, with epileptic seizures associated with Dravet syndrome or\plain\cf10\f51\fs20\qj Lennox-Gastaut syndrome (LGS). The study consists of a four to six-week screening period to establish baseline seizure\plain\cf10\f51\fs20\qj frequency followed by a 20-week treatment period that includes an 8-week dose optimization period and a 12-week\plain\cf10\f51\fs20\qj maintenance period. The primary endpoint is the change from baseline in seizure frequency in patients treated with OV935\plain\cf10\f51\fs20\qj compared to placebo by disorder (Dravet, LGS). The secondary endpoints include safety, tolerability, and pharmacokinetic (PK)\plain\cf10\f51\fs20\qj assessments as well as the percentage of patients considered treatment responders, changes in Clinician\u8217?s Clinical Global\plain\cf10\f51\fs20\qj Impressions of Severity and Change (CGI-S/C), and correlation of OV935 concentration with plasma\~24HC\~levels. ELEKTRA is\plain\cf10\f51\fs20\qj expected to enroll 126 pediatric patients at approximately 45 clinical trial sites in\~\plain\cf1\f51\fs20\qj North America\plain\cf10\f51\fs20\qj ,\~\plain\cf1\f51\fs20\qj Israel\plain\cf10\f51\fs20\qj ,\~\plain\cf1\f51\fs20\qj Australia\plain\cf10\f51\fs20\qj , EU Countries,\plain\cf10\f51\fs20\qj and\~\plain\cf1\f51\fs20\qj China\plain\cf10\f51\fs20\qj . At the end of the study, eligible patients, including those in the placebo arm, have the option to roll over into the\plain\cf10\f51\fs20\qj ENDYMION study, an open-label extension trial for patients with dEE who have previously participated in an OV935 clinical\plain\cf10\f51\fs20\qj trial.\~\par\pard\plain\sb220\cf10\f51\fs20\i\qj ARCADE\par\pard\plain\sb220\fi528\cf10\f51\fs20\qj ARCADE is a Phase 2, multi-center, open-label, pilot study that will evaluate the treatment of OV935 in patients, aged 2\plain\cf10\f51\fs20\qj to 35 years old, with epileptic seizures associated with CDKL5 Deficiency Disorder (CDD) or Duplication 15q (Dup15q)\plain\cf10\f51\fs20\qj syndrome. The primary endpoint is the change in motor seizure frequency in patients treated with OV935 by disorder type (either\plain\cf10\f51\fs20\qj CDD or Dup15q). The key secondary endpoints include safety and tolerability, including percentage of participants considered\plain\cf10\f51\fs20\qj treatment responders, change in CGI-S/C, and correlation of OV935 concentration and plasma\~24HC\~levels.\par\pard\plain\sb220\fi528\cf10\f51\fs20\qj ARCADE is expected to enroll approximately 15 children with each condition at clinical trial sites in\~the United States.\plain\cf10\f51\fs20\qj This study consists of a four to six-week screening period to establish baseline seizure frequency followed by a 20-week\plain\cf10\f51\fs20\qj treatment period (8-week dose optimization and 12-week maintenance period). At the end of treatment, eligible patients can roll\plain\cf10\f51\fs20\qj over into the ENDYMION study.\~\par\pard\plain\sb220\cf1\f51\fs20\b\qj License and Collaboration Agreements\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj License Agreement with H. Lundbeck A/S\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In March 2015, we entered into a license agreement with Lundbeck, or the Lundbeck agreement, pursuant to which we\plain\cf1\f51\fs20\qj obtained from Lundbeck an exclusive (subject to certain reserved non-commercial rights), worldwide license to develop,\plain\cf1\f51\fs20\qj manufacture, and commercialize OV101, also known as gaboxadol, for the treatment of human disease. Under the Lundbeck\plain\cf1\f51\fs20\qj agreement, we are responsible for and will use commercially reasonable efforts to carry out all future development and\plain\cf1\f51\fs20\qj commercialization of OV101. Initially, we will purchase OV101 compound from Lundbeck\u8217?s existing inventory at a\plain\cf1\f51\fs20\qj specified price. Following the depletion of the existing inventory, we may purchase the compound from a third party or, if the\plain\cf1\f51\fs20\qj parties agree, Lundbeck may continue to supply the compound to us. We are also obligated to make certain\plain\cf1\f51\fs20\qj manufacturing-related payments to Lundbeck, including for its preparation of a drug master file for OV101. We granted\plain\cf1\f51\fs20\qj Lundbeck a right of first negotiation if we decide at any time to seek a partner to develop or commercialize OV101 in one or\plain\cf1\f51\fs20\qj more specified countries.{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In connection with the Lundbeck agreement, we issued 489,756\~shares of our common stock to Lundbeck. We also agreed\plain\cf1\f51\fs20\qj to pay to Lundbeck milestone payments up to an aggregate of $181.0\~million upon the achievement of certain global\plain\cf1\f51\fs20\qj development, regulatory and sales milestone events. In addition, if we successfully develop and commercialize OV101, we will\plain\cf1\f51\fs20\qj be obligated to pay to Lundbeck tiered royalties in the range of low to middle teens based on the net sales of OV101, subject to\plain\cf1\f51\fs20\qj certain reductions for generic product sales and for royalties paid for licenses to third party intellectual property. In the event that\plain\cf1\f51\fs20\qj we commercialize OV101 with a partner in China, Japan or South Korea, each, an Asian Partner, we will instead share with\plain\cf1\f51\fs20\qj Lundbeck specified percentages of\par\pard\plain\sb264\cf1\f51\fs20\qc 25\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb220\cf1\f51\fs20\qj the payments we receive from the Asian Partner, including any upfront payment, milestone payments and royalties, provided that\plain\cf1\f51\fs20\qj we may deduct certain OV101 development expenses from the amounts owed to Lundbeck. Our obligation to make royalty\plain\cf1\f51\fs20\qj payments, and to share amounts received from Asian Partners, will expire on a country-by-country basis upon the later of the\plain\cf1\f51\fs20\qj expiration of the last solely owned licensed patent or 10 years after the first commercial sale. If Lundbeck manufactures OV101\plain\cf1\f51\fs20\qj compound for us after the expiration of the royalty term, we will pay to Lundbeck, in addition to the fully burdened cost of such\plain\cf1\f51\fs20\qj manufacture, a low, single digit manufacturing royalty on the net sales of OV101 manufactured by Lundbeck.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The Lundbeck agreement will continue until the expiration of all relevant royalty terms, and may be earlier terminated by\plain\cf1\f51\fs20\qj either party for the other party\u8217?s uncured material breach or insolvency. In addition, we can terminate the Lundbeck\plain\cf1\f51\fs20\qj agreement upon advance notice for convenience at any time prior to first regulatory approval of OV101. If the Lundbeck\plain\cf1\f51\fs20\qj agreement is terminated by us for convenience or by Lundbeck for our breach or insolvency, the OV101 compound will revert to\plain\cf1\f51\fs20\qj Lundbeck and we will grant Lundbeck an exclusive license to develop and commercialize OV101; such license will be\plain\cf1\f51\fs20\qj royalty-bearing if we filed an application for regulatory approval prior to termination. If we terminate the Lundbeck agreement\plain\cf1\f51\fs20\qj for Lundbeck\u8217?s breach or insolvency, our license will continue and our obligations to make royalty payments to Lundbeck\plain\cf1\f51\fs20\qj and to share Asian Partner payments with Lundbeck will continue but we will not be obligated to make further milestone\plain\cf1\f51\fs20\qj payments to Lundbeck or to purchase any additional quantities of OV101 compound from Lundbeck\u8217?s existing inventory.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj License and Collaboration Agreement with Takeda\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In January 2017, we entered into a license and collaboration agreement with Takeda, or the Takeda license agreement. All\plain\cf1\f51\fs20\qj activities of the collaboration regarding OV935 will be guided by the Takeda/Ovid \u8220?One Team\u8221? concept, an\plain\cf1\f51\fs20\qj integrated and interdisciplinary team from both companies devoted to the successful advancement of OV935 across rare epilepsy\plain\cf1\f51\fs20\qj syndromes. Pursuant to the Takeda license agreement, we will take the lead in clinical development activities and\plain\cf1\f51\fs20\qj commercialization of the compound OV935 and products containing this compound (as well as certain other similar compounds,\plain\cf1\f51\fs20\qj including any prodrug where TAK-935 is the primary pharmacologically active metabolite) for the treatment of certain rare\plain\cf1\f51\fs20\qj neurological diseases in the United States, Canada, the European Union and Israel. Takeda will take the lead in\plain\cf1\f51\fs20\qj commercialization of OV935 in Japan and has the option to lead in Asia and the rest of the world, or the Takeda Territory.\plain\cf1\f51\fs20\qj While we and Takeda have agreed to initially focus on certain rare neurological disorders, the scope of the collaboration may in\plain\cf1\f51\fs20\qj the future include other mutually agreed upon rare neurological disorders.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Under the Takeda license agreement, Takeda granted to us an exclusive license in our territory under certain patents and\plain\cf1\f51\fs20\qj other intellectual property controlled by Takeda to commercialize OV935 and products containing OV935 for the treatment of\plain\cf1\f51\fs20\qj certain rare neurological disorders. Takeda also granted to us a worldwide, co-exclusive license to develop, manufacture and\plain\cf1\f51\fs20\qj otherwise exploit (but not commercialize) OV935 and products containing OV935 for the treatment of certain rare neurological\plain\cf1\f51\fs20\qj disorders.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Under the Takeda license agreement, we granted to Takeda an exclusive license in the Takeda Territory under certain\plain\cf1\f51\fs20\qj patents and other intellectual property controlled by us to commercialize OV935 and products containing OV935 for the treatment\plain\cf1\f51\fs20\qj of certain rare neurological disorders. We also granted to Takeda a worldwide, co-exclusive license to develop, manufacture and\plain\cf1\f51\fs20\qj otherwise exploit (but not commercialize) OV935 and products containing OV935 for the treatment of certain rare neurological\plain\cf1\f51\fs20\qj disorders and a co-exclusive license in certain countries to commercialize OV935 and products containing OV935 for the\plain\cf1\f51\fs20\qj treatment of certain rare neurological disorders that are subsequently included in the collaboration.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We and Takeda will collaborate in the development of OV935. Pursuant to the terms of the Takeda license agreement, each\plain\cf1\f51\fs20\qj party is required to use commercially reasonable efforts to develop OV935 for the treatment of certain rare neurological disorders\plain\cf1\f51\fs20\qj in accordance with a mutually agreed upon development plan. We are primarily responsible for activities related to the\plain\cf1\f51\fs20\qj development of OV935, and as such Takeda will transition certain development activities to us. Takeda is initially responsible for\plain\cf1\f51\fs20\qj regulatory activities in all countries (excluding Israel). We are initially responsible for regulatory activities in Israel, and, upon\plain\cf1\f51\fs20\qj regulatory approval in the United States, Canada, and the European Union, we will assume responsibility for further regulatory\plain\cf1\f51\fs20\qj activities in such jurisdictions.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We and Takeda will collaborate in the commercialization of OV935. Pursuant to the terms of the Takeda license\plain\cf1\f51\fs20\qj agreement, each party is required to use commercially reasonable efforts to commercialize OV935 for the treatment of certain\plain\cf1\f51\fs20\qj rare neurological disorders in its territory. We are responsible for commercialization of OV935 in the United States, Canada, the\plain\cf1\f51\fs20\qj European Union and Israel, and Takeda is responsible for commercialization of OV935 in Japan, and has the first right to elect to\plain\cf1\f51\fs20\qj commercialize the products in the Takeda Territory. Additionally, Takeda has the right to jointly commercialize the products with\plain\cf1\f51\fs20\qj us in the United States and/or the European Union for any additional mutually agreed upon rare neurological indication.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Under the Takeda license agreement, we and Takeda will initially share equally all development and commercialization\plain\cf1\f51\fs20\qj costs and expenses prior to launch of a product and all revenues and commercialization costs and expenses after launch. In the\plain\cf1\f51\fs20\qj event that we and Takeda agree to expand the scope of the collaboration to include additional rare neurological disorders, either\plain\cf1\f51\fs20\qj party may elect not to fund all or a portion of the development of such indication, in which case such party\u8217?s overall share\plain\cf1\f51\fs20\qj of revenues and commercialization costs and expenses after launch of a product may be reduced under certain circumstances.\par\pard\plain\sb264\cf1\f51\fs20\qc 26\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj During the period commencing on the effective date of the Takeda license agreement, we and Takeda have both agreed that\plain\cf1\f51\fs20\qj we will not, directly or indirectly, and will cause all of our respective affiliates, not to, alone or with others, commercialize any\plain\cf1\f51\fs20\qj competing product in the field of rare neurological disorders. For these purposes, a competing product is any product or\plain\cf1\f51\fs20\qj compound directed against CH24H as its primary, intended mode of action. If, during such period, we or any of our affiliates is\plain\cf1\f51\fs20\qj acquired by a third party that is commercializing a competing product, then we must divest our interest or terminate the\plain\cf1\f51\fs20\qj commercialization of the competing product or cause our affiliate to do so.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The Takeda license agreement will expire upon the cessation of commercialization of the products by both us and Takeda.\plain\cf1\f51\fs20\qj Either party may terminate the Takeda license agreement as a result of the other party\u8217?s uncured material breach or\plain\cf1\f51\fs20\qj insolvency, for safety reasons, or, after completion of the first proof of mechanism clinical trial, for convenience. Takeda may\plain\cf1\f51\fs20\qj terminate the Takeda license agreement for our (or our sublicensee\u8217?s) challenge to the patents licensed under the Takeda\plain\cf1\f51\fs20\qj license agreement. If the agreement is terminated by Takeda for our material breach, bankruptcy or patent challenge or by us for\plain\cf1\f51\fs20\qj convenience or safety reasons, our rights to the products will cease, we will transition all activities related to the products to\plain\cf1\f51\fs20\qj Takeda, and we will grant Takeda an exclusive, royalty-bearing license under certain patents and other intellectual property\plain\cf1\f51\fs20\qj controlled by us to commercialize OV935 and products containing OV935 for the treatment of certain rare neurological disorders.\plain\cf1\f51\fs20\qj If the agreement is terminated by us for Takeda\u8217?s material breach or bankruptcy or by Takeda for convenience or safety\plain\cf1\f51\fs20\qj reasons, Takeda\u8217?s rights to the products will cease, Takeda will transition all activities related to the products to us, and\plain\cf1\f51\fs20\qj Takeda will grant us an exclusive, royalty-bearing license under certain patents and other intellectual property controlled by\plain\cf1\f51\fs20\qj Takeda to commercialize OV935 and products containing OV935 for the treatment of certain rare neurological disorders.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Under the Takeda license agreement, in the event of an acquisition of us by certain types of acquirers prior to the final\plain\cf1\f51\fs20\qj dosing of a patient in the first Phase 3 trial, Takeda would have the right to elect to take over all development and\plain\cf1\f51\fs20\qj commercialization activities with respect to the products, so long as Takeda at such time has (or will have) sufficient commercial\plain\cf1\f51\fs20\qj infrastructure to commercialize the products. Even if Takeda exercises such right to take over all development and\plain\cf1\f51\fs20\qj commercialization activities with respect to the products, we and Takeda will continue to share equally all development and\plain\cf1\f51\fs20\qj commercialization costs and expenses prior to launch of a product and all revenues and commercialization costs and expenses\plain\cf1\f51\fs20\qj after launch, unless otherwise set forth in the agreement.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In connection with the Takeda license agreement and in consideration of certain license rights granted to us by Takeda, we\plain\cf1\f51\fs20\qj issued 1,781,996 shares of our Series B-1 convertible preferred stock to Takeda. The shares of Series B-1 preferred stock held\plain\cf1\f51\fs20\qj by Takeda automatically converted into 1,781,996 shares of our common stock in May 2017. Under the Takeda license\plain\cf1\f51\fs20\qj agreement, we are obligated to pay Takeda future payments if and when certain milestones are achieved. Upon the first patient\plain\cf1\f51\fs20\qj enrollment in the first Phase 3 trial for the first of the initial disorders we and Takeda are focusing on, we are obligated to issue\plain\cf1\f51\fs20\qj to Takeda the number of unregistered shares of our common stock equal to the lesser of (a) 8% of our outstanding capital stock\plain\cf1\f51\fs20\qj on the issuance date or (b) $50.0\~million divided by the applicable share price, unless certain events occur. In the event such\plain\cf1\f51\fs20\qj payment would cause Takeda to own over 19.99% of our outstanding capital stock or other events occur, such payment must be\plain\cf1\f51\fs20\qj paid in cash. The remaining potential global commercial and regulatory milestone payments equal approximately $35.0\~million\plain\cf1\f51\fs20\qj and can be satisfied in cash or unregistered shares of our common stock at our election.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Northwestern License\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In December 2016, we entered into a license agreement with Northwestern University, or Northwestern, pursuant to which\plain\cf1\f51\fs20\qj Northwestern granted us an exclusive, worldwide license to patent rights in certain inventions, or the Northwestern Patent Rights,\plain\cf1\f51\fs20\qj which relate to a specific compound and related methods of use for such compound, along with certain Know-How related to the\plain\cf1\f51\fs20\qj practice of the inventions claimed in the Northwestern Patents.\~\~\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Under the Northwestern agreement, we were granted exclusive rights to research, develop, manufacture and commercialize\plain\cf1\f51\fs20\qj products utilizing the Northwestern Patent Rights for all uses. We have agreed that we will not use the Northwestern Patent\plain\cf1\f51\fs20\qj Rights to develop any products for the treatment of cancer, but Northwestern may not grant rights in the technology to others for\plain\cf1\f51\fs20\qj use in cancer. We also have an option, exercisable during the term of the agreement to an exclusive license under certain\plain\cf1\f51\fs20\qj intellectual property rights covering novel compounds with the same or similar mechanism of action as the primary compound\plain\cf1\f51\fs20\qj that is the subject of the license agreement.\~\~Northwestern has retained the right, on behalf of itself and other non-profit\plain\cf1\f51\fs20\qj institutions, to use the Northwestern Patent Rights and practice the inventions claimed therein for educational and research\plain\cf1\f51\fs20\qj purposes and to publish information about the inventions covered by the Northwestern Patent Rights.\~\~\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Upon entry into the Northwestern agreement, we paid an upfront non-creditable one-time license issuance fee of $75,000,\plain\cf1\f51\fs20\qj and we are required to pay an annual license maintenance fee of $20,000, which will be creditable against any royalties payable\plain\cf1\f51\fs20\qj to Northwestern following first commercial sale of licensed products under the agreement.\~\~We are responsible for all ongoing\plain\cf1\f51\fs20\qj costs of filing, prosecuting and maintaining the Northwestern Patents, but we also have the right to control such activities using\plain\cf1\f51\fs20\qj our own patent counsel.\~\~In consideration for the rights granted to us under the Northwestern agreement, we are required to pay\plain\cf1\f51\fs20\qj to Northwestern up to an aggregate of $5.3 million upon the achievement of certain development and regulatory milestones for\plain\cf1\f51\fs20\qj the first product covered by the Northwestern Patents, and, upon commercialization of any such products, will be required to pay\plain\cf1\f51\fs20\qj to Northwestern a tiered royalty on net sales of such products by the Company, its affiliates or sublicensees, at percentages in the\plain\cf1\f51\fs20\qj low to mid single-digits, subject to standard reductions and offsets.\~\~Our royalty obligations continue on a product-by-product\plain\cf1\f51\fs20\qj and country-by-country basis until the later of the expiration of the last-to-expire valid claim in a licensed patent covering the\plain\cf1\f51\fs20\qj applicable product in such country and 10 years following the first commercial sale of such product in such country.\~\~If Ovid\plain\cf1\f51\fs20\qj sublicenses a Northwestern Patent Right, it will be obligated to pay to Northwestern a specified percentage of sublicense revenue\plain\cf1\f51\fs20\qj received by us, ranging from the high single digits to the low-teens.\~\~\par\pard\plain\sb264\cf1\f51\fs20\qc 27\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The Northwestern agreement requires that we use commercially reasonable efforts to develop and commercialize at least\plain\cf1\f51\fs20\qj one product that is covered by the Northwestern Patent Rights.\~\~\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Unless earlier terminated, the Northwestern agreement will remain in force until the expiration of our payment obligations\plain\cf1\f51\fs20\qj thereunder.\~\~We have the right to terminate the agreement for any reason upon prior written notice or for an uncured material\plain\cf1\f51\fs20\qj breach by Northwestern.\~\~Northwestern may terminate the agreement for our uncured material breach or insolvency.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Sales and Marketing\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Given our stage of development, we have not yet established a commercial organization or distribution capabilities. We\plain\cf1\f51\fs20\qj plan to build focused capabilities in the United States and European Union to commercialize our development programs focused\plain\cf1\f51\fs20\qj on orphan disorders of the brain, where we believe the patient populations and medical specialists for the indications we are\plain\cf1\f51\fs20\qj targeting are sufficiently concentrated to allow us to effectively promote our product, if approved for commercial sale, with a\plain\cf1\f51\fs20\qj targeted sales team. In other markets for which commercialization may be less capital efficient for us, we may selectively pursue\plain\cf1\f51\fs20\qj strategic collaborations with third parties in order to maximize the commercial potential of our drug candidates.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Manufacturing and Supply\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We currently have no manufacturing facilities and we intend to use our collaborators and contract manufacturers for the\plain\cf1\f51\fs20\qj foreseeable future. However, certain members of our management have broad experience in manufacturing, which we believe\plain\cf1\f51\fs20\qj may provide a competitive advantage.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We currently rely on Lundbeck to provide the drug substance supply for our planned clinical trials in OV101. Pursuant to\plain\cf1\f51\fs20\qj the Lundbeck agreement, we agreed to purchase from Lundbeck, and Lundbeck agreed to sell to us, the entirety of their existing\plain\cf1\f51\fs20\qj inventory of the OV101 compound. We have purchased and imported a portion of this inventory, which was requalified by\plain\cf1\f51\fs20\qj Lundbeck, and expect that this supply will be sufficient to meet our needs through the completion of our planned Phase 2 trials\plain\cf1\f51\fs20\qj in Angelman syndrome and Fragile X syndrome. We further expect that Lundbeck\u8217?s remaining existing inventory will be\plain\cf1\f51\fs20\qj sufficient to meet our needs through the completion of all of our planned clinical trials in OV101 and potentially into\plain\cf1\f51\fs20\qj commercialization, if approved. Following the depletion of Lundbeck\u8217?s existing inventory, we may purchase the OV101\plain\cf1\f51\fs20\qj compound from a third party or, if the parties agree, Lundbeck may continue to supply the compound to us at the fully burdened\plain\cf1\f51\fs20\qj cost of manufacture. We have contracted with a third-party contract development and manufacturing organization to manufacture\plain\cf1\f51\fs20\qj the drug product for our planned and ongoing clinical trials in OV101, and we expect to engage another third party to package,\plain\cf1\f51\fs20\qj label and distribute the drug. We plan to continue to rely upon Lundbeck and/or one or more alternative contract manufacturers\plain\cf1\f51\fs20\qj to supply us with commercial quantities of drug substance and drug product supply, including for OV101, if approved.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We will continue to rely on Takeda to provide the drug product supply for our planned clinical trials in OV935 and, if\plain\cf1\f51\fs20\qj approved, drug substance supply for commercial use of OV935. We will be required to contract with a third-party development\plain\cf1\f51\fs20\qj and manufacturing organization to manufacture the drug product for our commercial use, and we expect to engage another third\plain\cf1\f51\fs20\qj party to package, label and distribute the drug.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Competition\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Currently, there are no therapies approved for the treatment of Angelman syndrome or Fragile X syndrome. However,\plain\cf1\f51\fs20\qj certain symptomatic treatments, including traditional anticonvulsants, sedatives and antianxiety drugs, are employed to lessen the\plain\cf1\f51\fs20\qj burden of these disorders. We believe SAGE Therapeutics, Inc., Marinus Pharmaceuticals, Inc. and Zynerba Pharmaceuticals, Inc.\plain\cf1\f51\fs20\qj are our most direct competitors with respect to OV101. We believe Zogenix, Inc., GW Pharmaceuticals plc, Sage Therapeutics,\plain\cf1\f51\fs20\qj Inc., Marinus Pharmaceuticals, Inc., Zynerba Pharmaceuticals, Inc. and PTC Therapeutics, Inc. are our most direct competitors\plain\cf1\f51\fs20\qj with respect to OV935. Biogen/Ionis, Roche, Agilix and GeneTx are working on genetic approaches to AS.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Drug development is highly competitive and subject to rapid and significant technological advancements. Our ability to\plain\cf1\f51\fs20\qj compete will significantly depend upon our ability to complete necessary clinical trials and regulatory approval processes, and\plain\cf1\f51\fs20\qj effectively market any drug that we may successfully develop. Our current and potential future competitors include\plain\cf1\f51\fs20\qj pharmaceutical and biotechnology companies, academic institutions and government agencies. The primary competitive factors\plain\cf1\f51\fs20\qj that will affect the commercial success of any drug candidate for which we may receive marketing approval include efficacy,\plain\cf1\f51\fs20\qj safety and tolerability profile, dosing convenience, price, coverage and reimbursement. Many of our existing or potential\plain\cf1\f51\fs20\qj competitors have substantially greater financial, technical and human resources than we do and significantly greater experience in\plain\cf1\f51\fs20\qj the discovery and development of drug candidates, as well as in obtaining regulatory approvals of those drug candidates in the\plain\cf1\f51\fs20\qj United States and in foreign countries.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Our current and potential future competitors also have significantly more experience commercializing drugs that have been\plain\cf1\f51\fs20\qj approved for marketing. Mergers and acquisitions in the pharmaceutical and biotechnology industries could result in even more\plain\cf1\f51\fs20\qj resources being concentrated among a small number of our competitors.\par\pard\plain\sb264\cf1\f51\fs20\qc 28\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Accordingly, our competitors may be more successful than us in obtaining regulatory approval for therapies and in\plain\cf1\f51\fs20\qj achieving widespread market acceptance of their drugs. It is also possible that the development of a cure or more effective\plain\cf1\f51\fs20\qj treatment method for the disorders we are targeting by a competitor could render our current or future drug candidates\plain\cf1\f51\fs20\qj non-competitive or obsolete or reduce the demand for our drug candidates before we can recover our development and\plain\cf1\f51\fs20\qj commercialization expenses.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Intellectual Property\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Our commercial success depends in part on our ability to obtain and maintain proprietary protection for our current and\plain\cf1\f51\fs20\qj future drug candidates, novel discoveries, product development technologies and know-how, to operate without infringing on the\plain\cf1\f51\fs20\qj proprietary rights of others and to prevent others from infringing our proprietary rights. Our policy is to seek to protect our\plain\cf1\f51\fs20\qj proprietary position by, among other methods, filing or in-licensing U.S. and foreign patents and patent applications related to\plain\cf1\f51\fs20\qj technology, inventions and improvements that are important to the development and implementation of our business. We also rely\plain\cf1\f51\fs20\qj on trademarks, trade secrets, copyright protection, know-how, continuing technological innovation and potential in-licensing\plain\cf1\f51\fs20\qj opportunities to develop and maintain our proprietary position. For example, the proprietary map of disease-relevant biological\plain\cf1\f51\fs20\qj pathways underlying orphan disorders of the brain that we developed would not be appropriate for patent protection and, as a\plain\cf1\f51\fs20\qj result, we rely on trade secrets to protect this aspect of our business.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj While we seek broad coverage under our existing patent applications, there is always a risk that an alteration to the product\plain\cf1\f51\fs20\qj or process may provide sufficient basis for a competitor to avoid infringement claims. In addition, the coverage claimed in a\plain\cf1\f51\fs20\qj patent application can be significantly reduced before a patent is issued and courts can reinterpret patent scope after issuance.\plain\cf1\f51\fs20\qj Moreover, many jurisdictions including the United States permit third parties to challenge issued patents in administrative\plain\cf1\f51\fs20\qj proceedings, which may result in further narrowing or even cancellation of patent claims. Moreover, we cannot provide any\plain\cf1\f51\fs20\qj assurance that any patents will be issued from our pending or any future applications or that any potentially issued patents will\plain\cf1\f51\fs20\qj adequately protect our intellectual property.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We have exclusively licensed a portfolio of issued U.S. and international patents from Lundbeck directed to polymorphic\plain\cf1\f51\fs20\qj forms of OV101 and their preparation, and these patents expire on dates ranging from 2025 to 2028. In addition, we have\plain\cf1\f51\fs20\qj exclusively licensed from Lundbeck a pending application directed to an OV101 manufacturing processes that, if issued, would\plain\cf1\f51\fs20\qj have a statutory expiration in 2036. We have also filed, and own, multiple patent families directed to methods of treatment and\plain\cf1\f51\fs20\qj formulations with OV101. In particular, we currently own issued U.S. patents directed to treatment of Angelman syndrome and\plain\cf1\f51\fs20\qj Fragile X syndrome with OV101 that expire in 2035, excluding any regulatory extensions. Additional issued patents and pending\plain\cf1\f51\fs20\qj applications are directed to methods of treating neurodegenerative diseases and developmental disorders. We intend to seek patent\plain\cf1\f51\fs20\qj protection for these inventions in numerous countries and regions including, among others, Europe, Australia, Canada, Mexico,\plain\cf1\f51\fs20\qj Israel, Japan, China, and Korea.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We licensed from Takeda a portfolio of U.S. and international patents and applications directed to the OV935 composition\plain\cf1\f51\fs20\qj of matter, and these patents and applications expire in 2032, excluding any regulatory extensions.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Individual patents extend for varying periods depending on the date of filing of the patent application or the date of patent\plain\cf1\f51\fs20\qj issuance and the legal term of patents in the countries in which they are obtained. Generally, utility patents issued for\plain\cf1\f51\fs20\qj applications filed in the United States are granted a term of 20 years from the earliest effective filing date of a non-provisional\plain\cf1\f51\fs20\qj patent application. In addition, in certain instances, a patent term can be extended to recapture a portion of the U.S. Patent and\plain\cf1\f51\fs20\qj Trademark Office, or the USPTO, delay in issuing the patent as well as a portion of the term effectively lost as a result of the\plain\cf1\f51\fs20\qj FDA regulatory review period. However, as to the FDA component, the restoration period cannot be longer than five years and\plain\cf1\f51\fs20\qj the total patent term including the restoration period must not exceed 14 years following FDA approval. The duration of foreign\plain\cf1\f51\fs20\qj patents varies in accordance with provisions of applicable local law, but typically is also 20 years from the earliest effective\plain\cf1\f51\fs20\qj filing date. The actual protection afforded by a patent may vary on a product by product basis, from country to country and can\plain\cf1\f51\fs20\qj depend upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related\plain\cf1\f51\fs20\qj extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Furthermore, we rely upon trade secrets and know-how and continuing technological innovation to develop and maintain\plain\cf1\f51\fs20\qj our competitive position. We seek to protect our proprietary information, in part, using confidentiality agreements with our\plain\cf1\f51\fs20\qj employees and consultants and any potential commercial partners and collaborators and invention assignment agreements with our\plain\cf1\f51\fs20\qj employees. We also have or intend to implement confidentiality agreements or invention assignment agreements with our selected\plain\cf1\f51\fs20\qj consultants and any potential commercial partners. These agreements are designed to protect our proprietary information and, in\plain\cf1\f51\fs20\qj the case of the invention assignment agreements, to grant us ownership of technologies that are developed through a relationship\plain\cf1\f51\fs20\qj with a third party. These agreements may be breached, and we may not have adequate remedies for any breach. In addition, our\plain\cf1\f51\fs20\qj trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our commercial\plain\cf1\f51\fs20\qj partners, collaborators, employees and consultants use intellectual property owned by others in their work for us, disputes may\plain\cf1\f51\fs20\qj arise as to the rights in related or resulting know-how and inventions.\par\pard\plain\sb264\cf1\f51\fs20\qc 29\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties. It is\plain\cf1\f51\fs20\qj uncertain whether the issuance of any third-party patent would require us to alter our development or commercial strategies, or\plain\cf1\f51\fs20\qj our drugs or processes, obtain licenses or cease certain activities. Our breach of any license agreements or failure to obtain a\plain\cf1\f51\fs20\qj license to proprietary rights that we may require to develop or commercialize our future drugs may have an adverse impact on\plain\cf1\f51\fs20\qj us. Since patent applications in the United States and certain other jurisdictions are maintained in secrecy for 18 months or\plain\cf1\f51\fs20\qj potentially longer, and since publication of discoveries in the scientific or patent literature often lags behind actual discoveries,\plain\cf1\f51\fs20\qj we cannot be certain of the priority of inventions covered by pending patent applications. Moreover, we may have to participate\plain\cf1\f51\fs20\qj in Interference, Derivation, Reexam, Post-Grant Review, Inter Partes Review, or Opposition proceedings brought by third parties\plain\cf1\f51\fs20\qj or declared by the USPTO.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Government Regulation\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and\plain\cf1\f51\fs20\qj burdensome requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs,\plain\cf1\f51\fs20\qj such as those we are developing. These agencies and other federal, state and local entities regulate, among other things, the\plain\cf1\f51\fs20\qj research and development, testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, approval,\plain\cf1\f51\fs20\qj advertising and promotion, distribution, post-approval monitoring and reporting, sampling and export and import of our drug\plain\cf1\f51\fs20\qj candidates.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj U.S. Government Regulation\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and its\plain\cf1\f51\fs20\qj implementing regulations. The process of obtaining regulatory approvals and the subsequent compliance with applicable federal,\plain\cf1\f51\fs20\qj state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources. Failure to\plain\cf1\f51\fs20\qj comply with the applicable U.S. requirements at any time during the product development process, approval process or after\plain\cf1\f51\fs20\qj approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA\u8217?s refusal to\plain\cf1\f51\fs20\qj approve pending New Drug Applications, or NDAs, withdrawal of an approval, imposition of a clinical hold, issuance of warning\plain\cf1\f51\fs20\qj letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of\plain\cf1\f51\fs20\qj government contracts, restitution, disgorgement or civil or criminal penalties.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The process required by the FDA before a drug may be marketed in the United States generally involves the following:
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the\plain\intbl\cf1\f51\fs20\qj FDA\u8217?s good laboratory practice, or GLP, regulations;\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj submission to the FDA of an IND which must become effective before human clinical trials may begin;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj approval by an independent institutional review board, or IRB, at each clinical site before each trial may be\plain\intbl\cf1\f51\fs20\qj initiated;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj performance of adequate and well controlled human clinical trials in accordance with good clinical practice, or\plain\intbl\cf1\f51\fs20\qj GCP, requirements to establish the safety and efficacy of the proposed drug product for each indication;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj submission to the FDA of an NDA;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj satisfactory completion of an FDA advisory committee review, if applicable;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh1125
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is\plain\intbl\cf1\f51\fs20\qj produced to assess compliance with current good manufacturing practice, or cGMP, requirements and to assure that\plain\intbl\cf1\f51\fs20\qj the facilities, methods and controls are adequate to preserve the drug\u8217?s identity, strength, quality and purity;\plain\intbl\cf1\f51\fs20\qj and\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj FDA review and approval of the NDA.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Preclinical Studies\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Preclinical studies include laboratory evaluation of product chemistry, toxicity and formulation, as well as animal studies to\plain\cf1\f51\fs20\qj assess potential safety and efficacy. An IND sponsor must submit the results of the preclinical tests, together with manufacturing\plain\cf1\f51\fs20\qj information, analytical data and any available clinical data or literature, among other things, to the FDA as part of an IND. Some\plain\cf1\f51\fs20\qj preclinical testing may continue even after the IND is submitted. An IND automatically becomes effective 30 days after receipt\plain\cf1\f51\fs20\qj by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and\plain\cf1\f51\fs20\qj places the clinical trial on a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns\plain\cf1\f51\fs20\qj before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials to\plain\cf1\f51\fs20\qj commence.\par\pard\plain\sb264\cf1\f51\fs20\qc 30\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Clinical Trials\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Clinical trials involve the administration of the investigational new drug to human patients under the supervision of\plain\cf1\f51\fs20\qj qualified investigators in accordance with GCP requirements, which include the requirement that all research patients provide\plain\cf1\f51\fs20\qj their informed consent in writing for their participation in any clinical trial. Clinical trials are conducted under protocols detailing,\plain\cf1\f51\fs20\qj among other things, the objectives of the trial, the parameters to be used in monitoring safety and the effectiveness criteria to be\plain\cf1\f51\fs20\qj evaluated. A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of\plain\cf1\f51\fs20\qj the IND. In addition, an IRB at each institution participating in the clinical trial must review and approve the plan for any\plain\cf1\f51\fs20\qj clinical trial before it commences at that institution. Information about certain clinical trials must be submitted within specific\plain\cf1\f51\fs20\qj timeframes to the National Institutes of Health, or NIH, for public dissemination on their www.clinicaltrials.gov website.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj Phase 1 clinical trial: The drug is initially introduced into healthy human volunteers or patients with the target\plain\intbl\cf1\f51\fs20\qj disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if\plain\intbl\cf1\f51\fs20\qj possible, to gain an early indication of its effectiveness.\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj Phase 2 clinical trial: The drug is administered to a limited patient population to identify possible adverse effects\plain\intbl\cf1\f51\fs20\qj and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine\plain\intbl\cf1\f51\fs20\qj dosage tolerance and optimal dosage.\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj Phase 3 clinical trial: The drug is administered to an expanded patient population, generally at geographically\plain\intbl\cf1\f51\fs20\qj dispersed clinical trial sites, in well controlled clinical trials to generate enough data to statistically evaluate the\plain\intbl\cf1\f51\fs20\qj efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to\plain\intbl\cf1\f51\fs20\qj provide adequate information for the labeling of the product.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh1125\row}}}\pard\plain\sb220\fi528\cf1\f51\fs20\qj Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more\plain\cf1\f51\fs20\qj frequently if serious adverse events occur. Each of Phase 1, Phase 2 and Phase 3 clinical trials may not be completed\plain\cf1\f51\fs20\qj successfully within any specified period, or at all. Furthermore, the FDA or the sponsor may suspend or terminate a clinical trial\plain\cf1\f51\fs20\qj at any time on various grounds, including a finding that the research patients are being exposed to an unacceptable health risk.\plain\cf1\f51\fs20\qj Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted\plain\cf1\f51\fs20\qj in accordance with the IRB\u8217?s requirements or if the drug has been associated with unexpected serious harm to patients.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj A drug being studied in clinical trials may be made available to individual patients in certain circumstances. Pursuant to the\plain\cf1\f51\fs20\qj 21st Century Cures Act, or Cures Act, which was signed into law in December 2016, the manufacturer of an investigational drug\plain\cf1\f51\fs20\qj for a serious disease or condition is required to make available, such as by posting on its website, its policy on evaluating and\plain\cf1\f51\fs20\qj responding to requests for individual patient access to such investigational drug. This requirement applies on the later of 60\plain\cf1\f51\fs20\qj calendar days after the date of enactment of the Cures Act or the first initiation of a Phase 2 or Phase 3 trial of the\plain\cf1\f51\fs20\qj investigational drug.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Marketing Approval\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Assuming successful completion of the required clinical testing, the results of the preclinical studies and clinical trials,\plain\cf1\f51\fs20\qj together with detailed information relating to the product\u8217?s chemistry, manufacture, controls and proposed labeling, among\plain\cf1\f51\fs20\qj other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.\plain\cf1\f51\fs20\qj In most cases, the submission of an NDA is subject to a substantial application user fee. Under the Prescription Drug User Fee\plain\cf1\f51\fs20\qj Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of \u8220?filing\u8221?\plain\cf1\f51\fs20\qj of a standard NDA for a new molecular entity to review and act on the submission. This review typically takes twelve months\plain\cf1\f51\fs20\qj from the date the NDA is submitted to FDA because the FDA has approximately two months to make a \u8220?filing\u8221?\plain\cf1\f51\fs20\qj decision.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In addition, under the Pediatric Research Equity Act of 2003, or PREA, as amended and reauthorized, certain NDAs or\plain\cf1\f51\fs20\qj supplements to an NDA must contain data that are adequate to assess the safety and effectiveness of the drug for the claimed\plain\cf1\f51\fs20\qj indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for\plain\cf1\f51\fs20\qj which the product is safe and effective. The FDA may, on its own initiative or at the request of the applicant, grant deferrals for\plain\cf1\f51\fs20\qj submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the\plain\cf1\f51\fs20\qj pediatric data requirements.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The FDA also may require submission of a risk evaluation and mitigation strategy, or REMS, plan to ensure that the\plain\cf1\f51\fs20\qj benefits of the drug outweigh its risks. The REMS plan could include medication guides, physician communication plans,\plain\cf1\f51\fs20\qj assessment plans, or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk\plain\cf1\f51\fs20\qj minimization tools.\~\~The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before\plain\cf1\f51\fs20\qj accepting them for filing, to determine whether they are sufficiently complete to permit substantive review. The FDA may\plain\cf1\f51\fs20\qj request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the\plain\cf1\f51\fs20\qj additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the\plain\cf1\f51\fs20\qj submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA reviews an NDA to determine,\plain\cf1\f51\fs20\qj among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed,\plain\cf1\f51\fs20\qj packaged or held meets standards designed to assure the product\u8217?s continued safety, quality and purity.\par\pard\plain\sb264\cf1\f51\fs20\qc 31\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The FDA may refer an application for a novel drug to an advisory committee. An advisory committee is a panel of\plain\cf1\f51\fs20\qj independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to\plain\cf1\f51\fs20\qj whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an\plain\cf1\f51\fs20\qj advisory committee, but it considers such recommendations carefully when making decisions.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured. The\plain\cf1\f51\fs20\qj FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with\plain\cf1\f51\fs20\qj cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally,\plain\cf1\f51\fs20\qj before approving an NDA, the FDA may inspect one or more clinical trial sites to assure compliance with GCP requirements.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and\plain\cf1\f51\fs20\qj inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some\plain\cf1\f51\fs20\qj cases, a complete response letter. A complete response letter generally contains a statement of specific conditions that must be\plain\cf1\f51\fs20\qj met in order to secure final approval of the NDA and may require additional clinical or preclinical testing in order for FDA to\plain\cf1\f51\fs20\qj reconsider the application. Even with submission of this additional information, the FDA ultimately may decide that the\plain\cf1\f51\fs20\qj application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA\u8217?s\plain\cf1\f51\fs20\qj satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes commercial marketing of the drug with\plain\cf1\f51\fs20\qj specific prescribing information for specific indications.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Even if the FDA approves a product, it may limit the approved indications for use of the product, require that\plain\cf1\f51\fs20\qj contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase\plain\cf1\f51\fs20\qj 4 clinical trials, be conducted to further assess a drug\u8217?s safety after approval, require testing and surveillance programs to\plain\cf1\f51\fs20\qj monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk\plain\cf1\f51\fs20\qj management mechanisms under a REMS, which can materially affect the potential market and profitability of the product. The\plain\cf1\f51\fs20\qj FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance\plain\cf1\f51\fs20\qj programs. After approval, some types of changes to the approved product, such as adding new indications, manufacturing\plain\cf1\f51\fs20\qj changes, and additional labeling claims, are subject to further testing requirements and FDA review and approval.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Orphan Drug Act\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Under the Orphan Drug Act of 1983, the FDA may grant orphan designation to a drug or biologic intended to treat a rare\plain\cf1\f51\fs20\qj disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or\plain\cf1\f51\fs20\qj more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing\plain\cf1\f51\fs20\qj and making available in the United States a drug for this type of disease or condition will be recovered from sales in the United\plain\cf1\f51\fs20\qj States for that drug. Orphan drug designation must be requested before submitting an NDA. After the FDA grants orphan drug\plain\cf1\f51\fs20\qj designation, the name of the sponsor, identity of the drug or biologic and its potential orphan use are disclosed publicly by the\plain\cf1\f51\fs20\qj FDA. The orphan drug designation does not shorten the duration of the regulatory review or approval process, but does provide\plain\cf1\f51\fs20\qj certain advantages, such as a waiver of PDUFA fees, enhanced access to FDA staff and potential waiver of pediatric research\plain\cf1\f51\fs20\qj requirements.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj If a product that has orphan drug designation subsequently receives the first FDA approval for the disease for which it has\plain\cf1\f51\fs20\qj such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other\plain\cf1\f51\fs20\qj applications, including a full NDA, to market the same drug or biologic for the same indication for seven years, except in limited\plain\cf1\f51\fs20\qj circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity. Orphan drug exclusivity\plain\cf1\f51\fs20\qj does not prevent FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic\plain\cf1\f51\fs20\qj for a different disease or condition. Among the other benefits of orphan drug designation are tax credits for certain research and a\plain\cf1\f51\fs20\qj waiver of the application user fee. A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use\plain\cf1\f51\fs20\qj that is broader than the indication for which it received orphan designation. In addition, exclusive marketing rights in the United\plain\cf1\f51\fs20\qj States may be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is\plain\cf1\f51\fs20\qj unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The FDA granted orphan drug designation for OV101 for the treatment of Angelman syndrome and for the treatment of\plain\cf1\f51\fs20\qj Fragile X syndrome in September 2016 and October 2017, respectively. The FDA granted orphan drug designation for OV935\plain\cf1\f51\fs20\qj for the treatment of Dravet syndrome and Lennox-Gastaut syndrome both in December 2017.\~\~We intend to pursue orphan drug\plain\cf1\f51\fs20\qj designation for OV101 in additional indications, as well as for OV935 and potential other future drug candidates as we deem it\plain\cf1\f51\fs20\qj appropriate. Even if we were to obtain orphan drug designation for a drug candidate, we may not obtain orphan exclusivity and\plain\cf1\f51\fs20\qj that exclusivity may not effectively protect the drug from the competition of different drugs for the same condition, which could\plain\cf1\f51\fs20\qj be approved during the exclusivity period.\par\pard\plain\sb264\cf1\f51\fs20\qc 32\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj Post-Approval Requirements\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the\plain\cf1\f51\fs20\qj FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution,\plain\cf1\f51\fs20\qj advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the approved\plain\cf1\f51\fs20\qj product, such as adding new indications or other labeling claims are subject to prior FDA review and approval. There also are\plain\cf1\f51\fs20\qj continuing, annual user fee requirements for any marketed products and the establishments at which such products are\plain\cf1\f51\fs20\qj manufactured, as well as new application fees for supplemental applications with clinical data.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The FDA may impose a number of post-approval requirements as a condition of approval of an NDA. For example, the\plain\cf1\f51\fs20\qj FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the\plain\cf1\f51\fs20\qj product\u8217?s safety and effectiveness after commercialization.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are\plain\cf1\f51\fs20\qj required to register their establishments with the FDA and state agencies, and are subject to periodic unannounced inspections by\plain\cf1\f51\fs20\qj the FDA and these state agencies for compliance with cGMP requirements. Changes to the manufacturing process are strictly\plain\cf1\f51\fs20\qj regulated and often require prior FDA approval before being implemented. FDA regulations also require investigation and\plain\cf1\f51\fs20\qj correction of any deviations from cGMP requirements and impose reporting and documentation requirements upon the sponsor\plain\cf1\f51\fs20\qj and any third-party manufacturers that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time,\plain\cf1\f51\fs20\qj money, and effort in the area of production and quality control to maintain cGMP compliance.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards\plain\cf1\f51\fs20\qj is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems\plain\cf1\f51\fs20\qj with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to\plain\cf1\f51\fs20\qj comply with regulatory requirements, may result in mandatory revisions to the approved labeling to add new safety information;\plain\cf1\f51\fs20\qj imposition of post-market studies or clinical trials to assess new safety risks; or imposition of distribution or other restrictions\plain\cf1\f51\fs20\qj under a REMS program. Other potential consequences include, among other things:
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj fines, warning letters or holds on post-approval clinical trials;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of\plain\intbl\cf1\f51\fs20\qj product approvals;\cell{
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj product seizure or detention, or refusal to permit the import or export of products; or\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj injunctions or the imposition of civil or criminal penalties.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\sb220\fi528\cf1\f51\fs20\qj The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. Drugs\plain\cf1\f51\fs20\qj may be promoted only for the approved indications and in accordance with the provisions of the approved label. The FDA and\plain\cf1\f51\fs20\qj other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found\plain\cf1\f51\fs20\qj to have improperly promoted off-label uses may be subject to significant liability.\par\pard\plain\sb264\cf1\f51\fs20\qc 33\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\cf1\f51\fs20\b\qj Coverage and Reimbursement\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Sales of our drug candidates, if approved, will depend, in part, on the extent to which such products will be covered by\plain\cf1\f51\fs20\qj third-party payors, such as government health care programs, commercial insurance and managed healthcare organizations. These\plain\cf1\f51\fs20\qj third-party payors are increasingly limiting coverage or reducing reimbursements for medical products and services. In addition,\plain\cf1\f51\fs20\qj the U.S. government, state legislatures and foreign governments have continued implementing cost-containment programs,\plain\cf1\f51\fs20\qj including price controls, restrictions on reimbursement and requirements for substitution of generic products. Third-party payors\plain\cf1\f51\fs20\qj decide which therapies they will pay for and establish reimbursement levels. Third-party payors often rely upon Medicare\plain\cf1\f51\fs20\qj coverage policy and payment limitations in setting their own coverage and reimbursement policies. However, decisions regarding\plain\cf1\f51\fs20\qj the extent of coverage and amount of reimbursement to be provided for any drug candidates that we develop will be made on a\plain\cf1\f51\fs20\qj payor-by-payor basis. Each payor determines whether or not it will provide coverage for a therapy, what amount it will pay the\plain\cf1\f51\fs20\qj manufacturer for the therapy, and on what tier of its formulary it will be placed. The position on a payor\u8217?s list of covered\plain\cf1\f51\fs20\qj drugs, or formulary, generally determines the co-payment that a patient will need to make to obtain the therapy and can strongly\plain\cf1\f51\fs20\qj influence the adoption of such therapy by patients and physicians. Adoption of price controls and cost-containment measures, and\plain\cf1\f51\fs20\qj adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and\plain\cf1\f51\fs20\qj results. Decreases in third-party reimbursement for our drug candidates or a decision by a third-party payor to not cover our\plain\cf1\f51\fs20\qj drug candidates could reduce physician usage of our drug candidates, once approved, and have a material adverse effect on our\plain\cf1\f51\fs20\qj sales, results of operations and financial condition.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Other Healthcare Laws\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Because of our current and future arrangements with healthcare professionals, principal investigators, consultants, customers\plain\cf1\f51\fs20\qj and third-party payors, we will also be subject to healthcare regulation and enforcement by the federal government and the states\plain\cf1\f51\fs20\qj and foreign governments in which we will conduct our business, including our clinical research, proposed sales, marketing and\plain\cf1\f51\fs20\qj educational programs. Failure to comply with these laws, where applicable, can result in the imposition of significant civil,\plain\cf1\f51\fs20\qj criminal, and administrative penalties.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj The U.S. laws that may affect our ability to operate, among others, include: the federal Health Insurance Portability and\plain\cf1\f51\fs20\qj Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health\plain\cf1\f51\fs20\qj Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected\plain\cf1\f51\fs20\qj health information; certain state laws governing the privacy and security of health information in certain circumstances, some of\plain\cf1\f51\fs20\qj which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same\plain\cf1\f51\fs20\qj effect, thus complicating compliance efforts; the federal Anti-Kickback Statute, which prohibits, among other things, individuals\plain\cf1\f51\fs20\qj or entities from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in exchange\plain\cf1\f51\fs20\qj for or to induce either the referral of an individual for, or the purchase, order or recommendation of, any good or service for\plain\cf1\f51\fs20\qj which payment may be made under federal healthcare programs such as the Medicare and Medicaid programs; federal false\plain\cf1\f51\fs20\qj claims laws which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented,\plain\cf1\f51\fs20\qj claims for payment from Medicare, Medicaid, or other third-party payors that are false or fraudulent; federal criminal laws that\plain\cf1\f51\fs20\qj prohibit executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;\plain\cf1\f51\fs20\qj the Physician Payments Sunshine Act, which requires manufacturers of drugs, devices, biologics, and medical supplies to report\plain\cf1\f51\fs20\qj annually to the U.S. Department of Health and Human Services information related to payments and other transfers of value to\plain\cf1\f51\fs20\qj physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, and ownership\plain\cf1\f51\fs20\qj and investment interests held by physicians and their immediate family members.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In addition, many states have similar laws and regulations, such as anti-kickback and false claims laws that may be broader\plain\cf1\f51\fs20\qj in scope and may apply regardless of payor, in addition to items and services reimbursed under Medicaid and other state\plain\cf1\f51\fs20\qj programs. Additionally, to the extent that our product is sold in a foreign country, we may be subject to similar foreign laws.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Healthcare Reform\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Current and future legislative proposals to further reform healthcare or reduce healthcare costs may result in lower\plain\cf1\f51\fs20\qj reimbursement for our products. The cost containment measures that payors and providers are instituting and the effect of any\plain\cf1\f51\fs20\qj healthcare reform initiative implemented in the future could significantly reduce our revenues from the sale of our products.{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj For example, implementation of the Patient Protection and Affordable Care Act, as amended by the Health Care and\plain\cf1\f51\fs20\qj Education Reconciliation Act, collectively the Affordable Care Act, or the PPACA, has substantially changed healthcare financing\plain\cf1\f51\fs20\qj and delivery by both governmental and private insurers, and significantly impacted the pharmaceutical industry. The PPACA,\plain\cf1\f51\fs20\qj among other things, established an annual, nondeductible fee on any entity that manufactures or imports certain specified branded\plain\cf1\f51\fs20\qj prescription drugs and biologic agents, revised the methodology by which rebates owed by manufacturers to the state and federal\plain\cf1\f51\fs20\qj government for covered outpatient drugs under the Medicaid Drug Rebate Program are calculated, increased the minimum\plain\cf1\f51\fs20\qj Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program, extended the Medicaid Drug Rebate\plain\cf1\f51\fs20\qj program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations, provided incentives to\plain\cf1\f51\fs20\qj programs that increase the federal government\u8217?s comparative effectiveness research and created a licensure frame work for\plain\cf1\f51\fs20\qj follow-on biologic products. Since its enactment there have been judicial and Congressional challenges to certain aspects of the\plain\cf1\f51\fs20\qj PPACA. Since January\~2017, President\par\pard\plain\sb264\cf1\f51\fs20\qc 34\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~\par\pard\plain\sb220\cf1\f51\fs20\qj Trump has signed two Executive Orders and other directives designed to delay the implementation of certain provisions of the\plain\cf1\f51\fs20\qj PPACA or otherwise circumvent some of the requirements for health insurance mandated by the PPACA. Concurrently, Congress\plain\cf1\f51\fs20\qj has considered legislation that would repeal or repeal and replace all or part of the PPACA. While Congress has not passed\plain\cf1\f51\fs20\qj comprehensive repeal legislation, two bills affecting the implementation of certain taxes under the PPACA have been signed into\plain\cf1\f51\fs20\qj law. The Tax Cuts and Jobs Act of 2017 includes a provision repealing, effective January 1, 2019, the tax-based shared\plain\cf1\f51\fs20\qj responsibility payment imposed by the PPACA on certain individuals who fail to maintain qualifying health coverage for all or\plain\cf1\f51\fs20\qj part of a year that is commonly referred to as the \u8220?individual mandate\u8221?. Additionally, on January 22, 2018,\plain\cf1\f51\fs20\qj President Trump signed a continuing resolution on appropriations for fiscal year 2018 that delayed the implementation of certain\plain\cf1\f51\fs20\qj PPACA-mandated fees, including the so-called \u8220?Cadillac\u8221? tax on certain high cost employer-sponsored insurance\plain\cf1\f51\fs20\qj plans, the annual fee imposed on certain health insurance providers based on market share,\~and the medical device excise tax on\plain\cf1\f51\fs20\qj non-exempt medical devices. Further, the Bipartisan Budget Act of 2018, or the BBA, among other things, amends the PPACA,\plain\cf1\f51\fs20\qj effective January 1, 2019, to increase from 50 percent to 70 percent the point-of-sale discount that is owed by pharmaceutical\plain\cf1\f51\fs20\qj manufacturers who participate in Medicare Part D and\plain\cf1\f51\fs20\qj to\plain\cf1\f51\fs20\qj close the coverage gap in most Medicare drug plans, commonly referred\plain\cf1\f51\fs20\qj to as the \u8220?donut hole\u8221?. Congress could consider additional legislation to repeal or repeal and replace other elements\plain\cf1\f51\fs20\qj of the PPACA. Thus, the full impact of the PPACA on our business remains unclear.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In addition, other legislative changes have been proposed and adopted since the PPACA was enacted. In August 2011, then\plain\cf1\f51\fs20\qj President Obama signed into law the Budget Control Act of 2011, which, among other things, created the Joint Select Committee\plain\cf1\f51\fs20\qj on Deficit Reduction to recommend to Congress proposals for spending reductions. The Joint Select Committee did not achieve a\plain\cf1\f51\fs20\qj targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, triggering the legislation\u8217?s automatic\plain\cf1\f51\fs20\qj reduction to several government programs. This includes reductions to Medicare payments to providers of 2% per fiscal year,\plain\cf1\f51\fs20\qj which went into effect in April 2013 and, due to subsequent legislative amendments, including the BBA, will remain in effect\plain\cf1\f51\fs20\qj through 2027 unless additional Congressional action is taken. Additionally, in January 2013, then President Obama signed into\plain\cf1\f51\fs20\qj law the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several providers and\plain\cf1\f51\fs20\qj increased the statute of limitations period for the government to recover overpayments to providers from three to five years. More\plain\cf1\f51\fs20\qj recently, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed\plain\cf1\f51\fs20\qj products. For example, there have been several recent Congressional inquiries and proposed and enacted federal and state\plain\cf1\f51\fs20\qj legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and\plain\cf1\f51\fs20\qj manufacturer patient programs, and reform government program reimbursement methodologies for drug products.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We expect that additional federal and state, as well as foreign, healthcare reform measures will be adopted in the future,\plain\cf1\f51\fs20\qj any of which could result in reduced demand for our products or additional pricing pressure.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Employees\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj As of December 31, 2018, we had 55 full-time employees, 33 of whom were primarily engaged in research and\plain\cf1\f51\fs20\qj development activities and 21 of whom had an MD or PhD degree. None of our employees is represented by a labor union and\plain\cf1\f51\fs20\qj we consider our employee relations to be good.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Facilities\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We lease the space for our principal executive offices, which are located at 1460 Broadway, New York, New York, on a\plain\cf1\f51\fs20\qj monthly basis. We believe that our facilities are adequate to meet our current needs.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Corporate and Other Information\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We were incorporated in Delaware in April 2014. Our principal executive offices are located at 1460 Broadway, Suite\plain\cf1\f51\fs20\qj 15044, New York, New York 10036 and our telephone number is (646)\~661-7661. Our corporate website address is\plain\cf1\f51\fs20\qj www.ovidrx.com. Information contained on or accessible through our website is not a part of this Annual Report, and the\plain\cf1\f51\fs20\qj inclusion of our website address in this Annual Report is an inactive textual reference only.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We file electronically with the Securities and Exchange Commission, or the SEC, our annual reports on Form 10-K,\plain\cf1\f51\fs20\qj Annual reports on Form 10-Q, current reports on Form 8-K, and amendments to those reports filed or furnished pursuant to\plain\cf1\f51\fs20\qj Section\~13(a) or 15(d) of the Exchange Act. We make available on our website at\plain\cf1\f51\fs20\qj www.ovidrx.com\plain\cf1\f51\fs20\qj under\plain\cf1\f51\fs20\qj \u8220?Investors,\u8221? free of charge, copies of these reports as soon as reasonably practicable after filing or furnishing these\plain\cf1\f51\fs20\qj reports with the SEC.\par\pard\plain\cf1\f51\fs20\qj \~\par\pard\plain\sb264\cf1\f51\fs20\qc 35\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart item_1_3_3}{\*\bkmkend item_1_3_3}{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}{\*\bkmkstart item_1a_risk_factors_12765393}{\*\bkmkend item_1a_risk_factors_12765393}\par\pard\plain\cf1\f51\fs20\b\qj Item\~1A. Risk Factors\par\pard\plain\sb220\fi528\cf1\f51\fs20\i\qj An investment in our securities involves a high degree of risk.\~You should carefully consider the following information\plain\cf1\f51\fs20\i\qj about these risks, together with the other information appearing elsewhere in this Annual Report on Form 10-K, including our\plain\cf1\f51\fs20\i\qj unaudited condensed financial statements and related notes hereto, before deciding to invest in our common stock. The\plain\cf1\f51\fs20\i\qj occurrence of any of the following risks could have a material adverse effect on our business, financial condition, results of\plain\cf1\f51\fs20\i\qj operations and future growth prospects or cause our actual results to differ materially from those contained in forward-looking\plain\cf1\f51\fs20\i\qj statements we have made in this report and those we may make from time to time. In these circumstances, the market price of\plain\cf1\f51\fs20\i\qj our common stock could decline and you may lose all or part of your investment. We cannot assure you that any of the events\plain\cf1\f51\fs20\i\qj discussed below will not occur.\par\pard\plain\sb220\cf1\f51\fs20\b\qj Risks Related to Our Financial Position and Need for Additional Capital\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj We have incurred significant operating losses since inception and anticipate that we will continue to incur substantial\plain\li44\cf1\f51\fs20\b\i\qj operating losses for the foreseeable future and may never achieve or maintain profitability.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Since inception in April 2014, we have incurred significant operating losses. Our net loss was $52.0 million for the year\plain\cf1\f51\fs20\qj ended December\~31, 2018. As of December\~31, 2018, we had an accumulated deficit of $152.7 million. We expect to continue to\plain\cf1\f51\fs20\qj incur significant expenses and increasing operating losses for the foreseeable future. Since inception, we have devoted\plain\cf1\f51\fs20\qj substantially all of our efforts to research and preclinical and clinical development of our drug candidates, as well as hiring\plain\cf1\f51\fs20\qj employees and building our infrastructure. It could be several years, if ever, before we have a commercialized drug. The net\plain\cf1\f51\fs20\qj losses we incur may fluctuate significantly from quarter to quarter and year to year. We anticipate that our expenses will increase\plain\cf1\f51\fs20\qj substantially if, and as, we:
\par\pard\plain
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\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj continue the ongoing and planned preclinical and clinical development of our drug candidates;\cell{
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\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj continue to build a portfolio of drug candidates through the acquisition or in-license of drugs, drug candidates or\plain\intbl\cf1\f51\fs20\qj technologies;\cell{
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\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj initiate preclinical studies and clinical trials for any additional drug candidates that we may pursue in the future;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj seek marketing approvals for our current and future drug candidates that successfully complete clinical trials;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj establish a sales, marketing and distribution infrastructure to commercialize any drug candidate for which we may\plain\intbl\cf1\f51\fs20\qj obtain marketing approval;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj develop, maintain, expand and protect our intellectual property portfolio;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj implement operational, financial and management systems; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj attract, hire and retain additional administrative, clinical, regulatory and scientific personnel.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}{\*\bkmkstart _hlk535573396_12765393}{\*\bkmkend _hlk535573396_12765393}\pard\plain\sb220\fi528\cf1\f51\fs20\qj In addition, because of the numerous risks and uncertainties associated with pharmaceutical products and development, we\plain\cf1\f51\fs20\qj are unable to accurately predict the timing or amount of increased expenses or when, or if, we will be able to achieve\plain\cf1\f51\fs20\qj profitability. Our expenses could increase and profitability could be further delayed if we decide to or are required by the U.S.\plain\cf1\f51\fs20\qj Food and Drug Administration, or FDA, or other regulatory authorities such as the European Medicines Agency, or EMA, to\plain\cf1\f51\fs20\qj perform studies or trials in addition to those currently expected, or if there are any delays in the development, or in the\plain\cf1\f51\fs20\qj completion of any planned or future preclinical studies or clinical trials of our current and future drug candidates. Even if we\plain\cf1\f51\fs20\qj complete the development and regulatory processes described above, we anticipate incurring significant costs associated with\plain\cf1\f51\fs20\qj launching and commercializing our current and future drug candidates.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Even if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis.\plain\cf1\f51\fs20\qj Our failure to become and remain profitable would decrease the value of our company and could impair our ability to raise\plain\cf1\f51\fs20\qj capital, maintain our research and development efforts, expand our business or continue our operations.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj We have a limited operating history and have never generated any revenue from drug sales. Our limited operating history\plain\li44\cf1\f51\fs20\b\i\qj may make it difficult to evaluate the success of our business to date and to assess our future viability.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We are a clinical-stage company founded in April 2014. Our operations have consumed substantial amounts of cash since\plain\cf1\f51\fs20\qj our inception, primarily due to organizing and staffing our company, business planning, raising capital, acquiring assets and\plain\cf1\f51\fs20\qj undertaking the development of OV101 and OV935. We have not yet demonstrated the ability to, obtain marketing approvals,\plain\cf1\f51\fs20\qj manufacture a commercial-scale drug or conduct sales and marketing activities necessary for successful commercialization.\plain\cf1\f51\fs20\qj Consequently, any predictions about our future success or viability may not be as accurate as they could be if we had more\plain\cf1\f51\fs20\qj experience developing drug candidates.\par\pard\plain\sb264\cf1\f51\fs20\qc 36\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Our ability to generate revenue from drug sales and achieve profitability depends on our ability, alone or with any current\plain\cf1\f51\fs20\qj or future collaborative partners, to successfully complete the development of, and obtain the regulatory approvals necessary to\plain\cf1\f51\fs20\qj commercialize, our current and future drug candidates. We do not anticipate generating revenue from drug sales for the next\plain\cf1\f51\fs20\qj several years, if ever. Our ability to generate revenue from drug sales depends heavily on our, or any current or future\plain\cf1\f51\fs20\qj collaborators\u8217?, success in:
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj timely and successfully completing preclinical and clinical development of our current and future drug candidates;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj obtaining regulatory approvals for our current and future drug candidates for which we successfully complete\plain\intbl\cf1\f51\fs20\qj clinical trials;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj launching and commercializing any drug candidates for which we obtain regulatory approval by establishing a sales\plain\intbl\cf1\f51\fs20\qj force, marketing and distribution infrastructure or, alternatively, collaborating with a commercialization partner;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj qualifying for coverage and adequate reimbursement by government and third-party payors for any drug candidates\plain\intbl\cf1\f51\fs20\qj for which we obtain regulatory approval, both in the United States and internationally;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj developing, validating and maintaining a commercially viable, sustainable, scalable, reproducible and transferable\plain\intbl\cf1\f51\fs20\qj manufacturing process for our current and future drug candidates that is compliant with current good manufacturing\plain\intbl\cf1\f51\fs20\qj practices, or cGMP;\cell{
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\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh878
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj establishing and maintaining supply and manufacturing relationships with third parties that can provide an adequate\plain\intbl\cf1\f51\fs20\qj amount and quality of drugs and services to support clinical development, as well as the market demand for our\plain\intbl\cf1\f51\fs20\qj current and future drug candidates, if approved;\cell{
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj obtaining market acceptance, if and when approved, of our current or any future drug candidates as a viable\plain\intbl\cf1\f51\fs20\qj treatment option by physicians, patients, third-party payors and others in the medical community;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
\par\pard\plain
{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj effectively addressing any competing technological and market developments;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj implementing additional internal systems and infrastructure, as needed;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj negotiating favorable terms in any collaboration, licensing or other arrangements into which we may enter and\plain\intbl\cf1\f51\fs20\qj performing our obligations pursuant to such arrangements;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj our ability to obtain and maintain orphan drug exclusivity for any of our current and future drug candidates for\plain\intbl\cf1\f51\fs20\qj which we obtain regulatory approval;\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh630
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trade secrets\plain\intbl\cf1\f51\fs20\qj and know-how\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh630\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj avoiding and defending against third-party interference or infringement claims; and\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}
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{\trowd\cellx432\cellx1116\cellx10800\trrh382
\pard\plain\intbl\sb132\cf1\f51\fs20\qj \~\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj \u8226?\cell\pard\plain\intbl\sb132\cf1\f51\fs20\qj securing appropriate pricing in the United States, the European Union and other countries.\cell{
{\trowd\cellx432\cellx1116\cellx10800\trrh382\row}}}\pard\plain\sb220\fi528\cf1\f51\fs20\qj We expect our financial condition and operating results to continue to fluctuate from quarter to quarter and year to year due\plain\cf1\f51\fs20\qj to a variety of factors, many of which are beyond our control. We will need to eventually transition from a company with a\plain\cf1\f51\fs20\qj research and development focus to a company capable of undertaking commercial activities. We may encounter unforeseen\plain\cf1\f51\fs20\qj expenses, difficulties, complications and delays and may not be successful in such a transition.\par\pard\plain\li44\sb220\cf1\f51\fs20\b\i\qj We will require additional capital to finance our operations, which may not be available on acceptable terms, if at all.\plain\li44\cf1\f51\fs20\b\i\qj Failure to obtain this necessary capital when needed may force us to delay, limit or terminate certain of our drug\plain\li44\cf1\f51\fs20\b\i\qj development efforts or other operations.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Our operations have consumed substantial amounts of cash since our inception. We expect our expenses to increase in\plain\cf1\f51\fs20\qj connection with our ongoing and planned activities, particularly as we continue to develop and commercialize our drug\plain\cf1\f51\fs20\qj candidates, in addition to costs associated with the acquisition or in-licensing of any additional drug candidates we may pursue.\plain\cf1\f51\fs20\qj Our expenses could increase beyond expectations if the FDA or other regulatory authorities require us to perform clinical and\plain\cf1\f51\fs20\qj other studies in addition to those that we currently anticipate. In addition, if we obtain marketing approval for our drug\plain\cf1\f51\fs20\qj candidates, we expect to incur significant expenses related to manufacturing, marketing, sales and distribution. Furthermore, we\plain\cf1\f51\fs20\qj expect to incur additional costs associated with operating as a public company.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We will require capital to pursue our preclinical and clinical activities, regulatory approval and the commercialization of\plain\cf1\f51\fs20\qj our current or future drug candidates. Even if we believe we have sufficient capital for our current or future operating plans, we\plain\cf1\f51\fs20\qj may seek additional capital if market conditions are favorable or if we have specific strategic considerations. Any additional\plain\cf1\f51\fs20\qj capital raising efforts may divert our management from their day-to-day activities, which may adversely affect our ability to\plain\cf1\f51\fs20\qj develop and commercialize our current and future drug candidates.\par\pard\plain\sb264\cf1\f51\fs20\qc 37\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj If we do not raise additional capital in sufficient amounts, or on terms acceptable to us, we may be prevented from\plain\cf1\f51\fs20\qj pursuing development and commercialization efforts, which will harm our business, operating results and prospects.\par\pard\plain\sb220\cf1\f51\fs20\b\i\qj Raising additional capital or acquiring or licensing assets by issuing equity or debt securities may cause dilution to our\plain\cf1\f51\fs20\b\i\qj stockholders, and raising funds through lending and licensing arrangements may restrict our operations or require us to\plain\cf1\f51\fs20\b\i\qj relinquish proprietary rights.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Until such time as we can generate substantial revenue from drug sales, if ever, we expect to finance our cash needs\plain\cf1\f51\fs20\qj through a combination of equity and debt financings, strategic alliances, and license and development agreements in connection\plain\cf1\f51\fs20\qj with any collaborations. We do not have any committed external source of funds. To the extent that we issue additional equity\plain\cf1\f51\fs20\qj securities, our stockholders may experience substantial dilution, and the terms of these securities may include liquidation or other\plain\cf1\f51\fs20\qj preferences that adversely affect your rights as a stockholder. In addition, we may issue equity or debt securities as consideration\plain\cf1\f51\fs20\qj for obtaining rights to additional compounds. For example, in our arrangement with Takeda, upon the achievement of a certain\plain\cf1\f51\fs20\qj development milestone, we will be obligated to issue to Takeda additional securities equal to up to 8% of our outstanding capital\plain\cf1\f51\fs20\qj stock in certain situations which will dilute our stockholders. In addition, further dilution may occur if we elect to issue shares of\plain\cf1\f51\fs20\qj common stock to Takeda as payment for the remaining potential global commercial and regulatory milestone payments, which\plain\cf1\f51\fs20\qj aggregate to approximately $35.0\~million.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Debt and equity financings, if available, may involve agreements that include covenants limiting or restricting our ability to\plain\cf1\f51\fs20\qj take specific actions, such as redeeming our shares, making investments, issuing additional equity, incurring additional debt,\plain\cf1\f51\fs20\qj making capital expenditures, declaring dividends or placing limitations on our ability to acquire, sell or license intellectual\plain\cf1\f51\fs20\qj property rights and other operating restrictions that could negatively impact our ability to conduct our business. If we raise\plain\cf1\f51\fs20\qj additional capital through future collaborations, strategic alliances or third-party licensing arrangements, we may have to\plain\cf1\f51\fs20\qj relinquish valuable rights to our intellectual property, future revenue streams, research programs or drug candidates, or grant\plain\cf1\f51\fs20\qj licenses on terms that may not be favorable to us.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj If we are unable to raise additional capital when needed, we may be required to delay, limit, reduce or terminate our drug\plain\cf1\f51\fs20\qj development or future commercialization efforts, or grant rights to develop and market drug candidates that we would otherwise\plain\cf1\f51\fs20\qj develop and market ourselves.\par\pard\plain\sb220\cf1\f51\fs20\b\i\qj We may be required to make significant payments in connection with our licenses of OV101 from Lundbeck and OV935 from\plain\cf1\f51\fs20\b\i\qj Takeda.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We acquired rights to OV101, pursuant to a license agreement with H. Lundbeck A/S (\u8220?Lundbeck\u8221?) in March\plain\cf1\f51\fs20\qj 2015 (the \u8220?Lundbeck agreement\u8221?). Under the Lundbeck agreement, we are subject to significant obligations,\plain\cf1\f51\fs20\qj including payment obligations upon achievement of specified milestones and royalties on drug sales, as well as other material\plain\cf1\f51\fs20\qj obligations. We are obligated to pay Lundbeck milestone payments up to an aggregate of $181.0\~million upon the achievement of\plain\cf1\f51\fs20\qj certain development, regulatory and sales milestone events. In addition, we are obligated to pay Lundbeck tiered royalties based\plain\cf1\f51\fs20\qj on net sales of\~OV101. If these payments become due under the terms of the Lundbeck agreement, we may not have sufficient\plain\cf1\f51\fs20\qj funds available to meet our obligations and our development efforts may be harmed.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We also acquired rights to OV935 pursuant to a license and collaboration agreement with Takeda (the \u8220?Takeda\plain\cf1\f51\fs20\qj collaboration\u8221?) in January 2017. Under the Takeda collaboration, we are obligated to pay Takeda future payments upon\plain\cf1\f51\fs20\qj achievement of specified milestones. Upon the first patient enrollment in the first Phase 3 trial for the first of the initial\plain\cf1\f51\fs20\qj indications we and Takeda are focusing on pursuant to the Takeda collaboration, we are obligated to issue to Takeda the number\plain\cf1\f51\fs20\qj of unregistered shares of our common stock equal to the lesser of (i) 8% of our outstanding capital stock on the issuance date or\plain\cf1\f51\fs20\qj (ii) $50.0\~million divided by the applicable share price, unless certain events occur. The remaining potential global commercial\plain\cf1\f51\fs20\qj and regulatory milestone payments equal approximately $35.0\~million and can be satisfied in cash or unregistered shares of our\plain\cf1\f51\fs20\qj common stock at our election, unless certain events occur in which Takeda can require us to pay such payments in cash. In the\plain\cf1\f51\fs20\qj event a payment settled in shares of our common stock would cause Takeda to own over 19.99% of our outstanding capital stock\plain\cf1\f51\fs20\qj or other events occur, such payment must be paid in cash. If these payments become due under the terms of the Takeda\plain\cf1\f51\fs20\qj collaboration and we can only pay, or choose to pay, these payments in cash, we may not have sufficient funds available to meet\plain\cf1\f51\fs20\qj our obligations and our development efforts may be harmed.\par\pard\plain\sb264\cf1\f51\fs20\qc 38\par\pard\plain\f0\fs4\par\pard\plain\f0\fs2\brdrt\brdrs\brdrw15\brdrcf2\brdrsp0\par\pard\plain\f0\fs4\par
\page\par\pard\plain\cf1\f51\fs20\ql \~{\*\bkmkstart _aeioulastrenderedpagebreakaeiou}{\*\bkmkend _aeioulastrenderedpagebreakaeiou}\par\pard\plain\sb220\cf1\f51\fs20\b\i\qj Our ability to use our net operating loss carryforwards and certain other tax attributes may be limited to offset future taxable\plain\cf1\f51\fs20\b\i\qj income may be subject to limitation\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Our net operating loss, or NOL, carryforwards could expire unused and be unavailable to offset future income tax liabilities\plain\cf1\f51\fs20\qj because of their limited duration or because of restrictions under U.S. tax law. Our NOLs generated in tax years ending on or\plain\cf1\f51\fs20\qj prior to December\~31, 2017 are only permitted to be carried forward for 20 years under applicable U.S. tax law. Under H.R. 1,\plain\cf1\f51\fs20\qj \u8220?An Act to provide for reconciliation pursuant to titles II and V of the concurrent resolution on the budget for fiscal year\plain\cf1\f51\fs20\qj 2018,\u8221? informally titled the Tax Cuts and Jobs Act, or the Tax Act, our federal NOLs generated in tax years ending after\plain\cf1\f51\fs20\qj December\~31, 2017 may be carried forward indefinitely, but the deductibility of federal NOLs generated in tax years beginning\plain\cf1\f51\fs20\qj after December\~31, 2017 is limited. It is uncertain if and to what extent various states will conform to the Tax Act.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj In addition, under Section\~382 and Section\~383 of the Internal Revenue Code of 1986, as amended, or the Code, and\plain\cf1\f51\fs20\qj corresponding provisions of state law, if a corporation undergoes an \u8220?ownership change,\u8221? which is generally defined\plain\cf1\f51\fs20\qj as a greater than 50% change, by value, in its equity ownership over a three-year period, the corporation\u8217?s ability to use\plain\cf1\f51\fs20\qj its\~pre-change\~NOL carryforwards and other\~pre-change\~tax attributes (such as research tax credits) to offset its post-change\plain\cf1\f51\fs20\qj income or taxes may be limited. We may have experienced ownership changes in the past and may experience ownership\plain\cf1\f51\fs20\qj changes in the future as a result of shifts in our stock ownership (some of which shifts are outside our control). As a result, if we\plain\cf1\f51\fs20\qj earn net taxable income, our ability to use our pre-change NOLs to offset such taxable income will be subject to limitations.\plain\cf1\f51\fs20\qj Similar provisions of state tax law may also apply to limit our use of accumulated state tax attributes. In addition, at the state\plain\cf1\f51\fs20\qj level, there may be periods during which the use of NOLs is suspended or otherwise limited, which could accelerate or\plain\cf1\f51\fs20\qj permanently increase state taxes owed.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Consequently, even if we achieve profitability, we may not be able to utilize a material portion of our NOL carryforwards\plain\cf1\f51\fs20\qj and certain other tax attributes, which could have a material adverse effect on cash flow and results of operations.\par\pard\plain\sb220\cf1\f51\fs20\b\i\qj Comprehensive tax reform legislation could adversely affect our business and financial condition.\par\pard\plain\sb220\fi792\cf1\f51\fs20\qj On December\~22, 2017, President Trump signed into law the Tax Act, which significantly revises the Code. The Tax\plain\cf1\f51\fs20\qj Act, among other things, reduces the corporate tax rate from a top marginal rate of 35% to a flat rate of 21%, repeals the\plain\cf1\f51\fs20\qj alternative minimum tax for corporations, limits the tax deduction for interest expense to 30% of adjusted taxable income (except\plain\cf1\f51\fs20\qj for certain small businesses), limits the deduction for NOLs carried forward from taxable years beginning after December\~31,\plain\cf1\f51\fs20\qj 2017 to 80% of current year taxable income, eliminates NOL carrybacks, imposes a\~one-time\~tax on offshore earnings at reduced\plain\cf1\f51\fs20\qj rates regardless of whether they are repatriated, eliminates U.S. tax on foreign earnings (subject to certain important exceptions),\plain\cf1\f51\fs20\qj allows immediate deductions for certain new investments instead of deductions for depreciation expense over time, and modifies\plain\cf1\f51\fs20\qj or repeals many business deductions and credits. Notwithstanding the reduction in the corporate income tax rate, the overall\plain\cf1\f51\fs20\qj impact of the Tax Act is uncertain and our business and financial condition could be adversely affected. In addition, it is\plain\cf1\f51\fs20\qj uncertain if and to what extent various states will conform to the Tax Act. The impact of the Tax Act on holders of our common\plain\cf1\f51\fs20\qj stock (including our Series\~A preferred stock and the underlying shares of common stock) is also uncertain and could be adverse.\plain\cf1\f51\fs20\qj We urge our stockholders to consult with their legal and tax advisors with respect to this legislation and the potential tax\plain\cf1\f51\fs20\qj consequences of investing in or holding our common stock\plain\cf1\f52\fs20\qj .\par\pard\plain\sb220\cf1\f51\fs20\b\qj Risks Related to the Development and Commercialization of Our Drug Candidates\par\pard\plain\sb220\cf1\f51\fs20\b\i\qj Our future success is dependent on the successful clinical development, regulatory approval and commercialization of our\plain\cf1\f51\fs20\b\i\qj current and future drug candidates. If we are not able to obtain required regulatory approvals, we will not be able to\plain\cf1\f51\fs20\b\i\qj commercialize our drug candidates, and our ability to generate revenue will be adversely affected.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj We do not have any drugs that have received regulatory approval. Our business is dependent on our ability to successfully\plain\cf1\f51\fs20\qj complete preclinical and clinical development of, obtain regulatory approval for, and, if approved, successfully commercialize our\plain\cf1\f51\fs20\qj current and future drug candidates in a timely manner. Activities associated with the development and commercialization of our\plain\cf1\f51\fs20\qj current and future drug candidates are subject to comprehensive regulation by the FDA and other regulatory agencies in the\plain\cf1\f51\fs20\qj United States and similar regulatory authorities outside the United States. Failure to obtain regulatory approval in the United\plain\cf1\f51\fs20\qj States or other jurisdictions would prevent us from commercializing and marketing our current and future drug candidates.\par\pard\plain\sb220\fi528\cf1\f51\fs20\qj Even if we obtain approval from the FDA and comparable foreign regulatory authorities for our current and future drug\plain\cf1\f51\fs20\qj candidates, any approval might contain significant limitations related to use restrictions for specified age groups, warnings,\plain\cf1\f51\fs20\qj precautions or contraindications, or may be subject to burdensome post-approval study or risk management requirements. If we\plain\cf1\f51\fs20\qj are unable to obtain regulatory approval, or any approval contains significant limitations, we may not be able to obtain sufficient\plain\cf1\f51\fs20\qj funding or generate sufficient revenue to continue the development of that drug candidate or any other drug candidate that we\plain\cf1\f51\fs20\qj may in-l